Glutamate: Functions, Regulation and Disorders : Functions, Regulation and Disorders [1 ed.] 9781619425675, 9781619425453

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Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Glutamate: Functions, Regulation and Disorders : Functions, Regulation and Disorders, Nova Science Publishers, Incorporated, 2012. ProQuest Ebook

Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Glutamate: Functions, Regulation and Disorders : Functions, Regulation and Disorders, Nova Science Publishers, Incorporated, 2012. ProQuest

NEUROSCIENCE RESEARCH PROGRESS

GLUTAMATE

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FUNCTIONS, REGULATION AND DISORDERS

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NEUROSCIENCE RESEARCH PROGRESS

GLUTAMATE FUNCTIONS, REGULATION AND DISORDERS

GOLDA CHAYAT Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved.

AND

AVITAL YEDIDYA EDITORS

Nova Science Publishers, Inc. New York Glutamate: Functions, Regulation and Disorders : Functions, Regulation and Disorders, Nova Science Publishers, Incorporated, 2012. ProQuest

Copyright © 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data Glutamate : functions, regulation, and disorders / [edited by] Golda Chayat and Avital Yedidya. p. cm. Includes index. ISBN 978-1-61942-567-5 (eBook) 1. Glutamic acid--Metabolism. 2. Glutamic acid--Physiological effect. I. Chayat, Golda. II. Yedidya, Avital. QP562.G5G54 2011 612.8--dc23 2011050077

Published by Nova Science Publishers, Inc. † New York

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CONTENTS vii

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Preface Chapter 1

Blood Glutamate Scavenging: Insight into Neuroprotection Alexander Zlotnik, Akiva Leibowitz and Matthew Boyko

1

Chapter 2

Glutamate and Schizophrenia Huey-Jen Chang, Hsien-Yuan Lane and Guochuan E. Tsai

35

Chapter 3

Extracellular Osmolarity Modulates Glutamate Uptake and Release in Neurons, Astrocytes and Synaptosomes Tatyana V. Waseem and Sergei V. Fedorovich

Chapter 4

Glutamate: A Global Regulator Santanu Palchaudhuri and Dhrubajyoti Chattopadhyay

Chapter 5

Calcium-Calmodulin Kinase Type II-Mediated Glutamatergic Plasticity Underlies Expression of Benzodiazepine-Withdrawal Anxiety Elizabeth I. Tietz and Damien E. Earl

Chapter 6

Chapter 7

67 87

105

The Role of Supraspinal GABA and Glutamate in the Mediation and Modulation of Pain Kieran Rea and David P. Finn

125

Glutamate Receptors of the Kainate Type: An Ion Channel Becoming a Metabotropic Receptor José Vicente Negrete-Díaz and Antonio Rodríguez-Moreno

169

Index

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189

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PREFACE Glutamate is purported to be the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system are glutamatergic, and it is estimated that over half of all brain synapses release this agent. In this book, the authors present current research in the study of the functions, regulation and disorders related to glutamate. Topics include glutamate-scavenging in the treatment of acute brain insults; the physiology of glutamate receptors in schizophrenia; how glutamate works as a neurotransmitter and the role of supraspinal GABA and glutamate in the mediation of pain. Chapter 1 - Several acute brain insults such as stroke, traumatic brain injury, meningitis, subarachnoid hemorrhage, and chronic neurodegenerative states such as Alzheimer’s disease and amyotrophic lateral sclerosis , are characterized by a deleterious excess of glutamate in brain’s extracellular fluids. Excess of glutamate in brain interstitium, facilitates stimulation of glutamate receptors, which in turn lead to cell swelling, apoptosis and neuronal death, thus exacerbating neurological outcome. The classic approach, was aimed at antagonizing the astrocytic and glial glutamate receptors. While being a potentially promising in animal models, this approach has failed to demonstrate sound clinical benefit. An alternative approach to eliminating excess glutamate from brains interstitial fluids and CSF has been proposed, derived from the discovery of brain capillary endothelial glutamate transporters. A naturally-occurring brain-to blood glutamate efflux facilitated by a gradient driven transport across these transporters, has been shown to eliminate excess glutamate from brain fluids. Blood glutamate scavengers enhance this naturally occurring mechanism, increasing the rate at which excess glutamate is cleared. Reduction of blood glutamate concentration in plasma establishes a new, more favorable concentration gradient, facilitating transport of excess glutamate from brains’ extracellular fluids into the blood. Numerous studies demonstrate a strong correlation between blood glutamate concentrations and the concentration in the brain’s extracellular fluid, thus suggesting that blood glutamate concentration might significantly affect glutamate concentration in brain. Recent studies have validated the effectiveness of the glutamate-scavenging approach in treatment of acute brain insults. Lower blood glutamate concentrations have been associated with improved neurological outcomes in both animal models and human studies. Conversely, elevated blood glutamate levels were associated with worse neurological outcomes. These findings lead to the notion that reducing elevated blood glutamate levels may play an important role in neuroprotection.

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Golda Chayat and Avital Yedidya

One of the proposed blood glutamate reduction mechanisms introduced initially, involved the metabolism of glutamate into Į-ketoglutarate. This naturally occurring enzymatic process is mediated by activation of resident plasma enzymes glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) in the presence of their respective coenzymes oxaloacetate and pyruvate. Further studies, based on blood glutamate reducing modalities other than oxaloacetate and pyruvate, have shown that additional mechanisms may be involved as well. These mechanisms share common physiological processes regulating blood glutamate levels. Acute stress response mediated via activation of ȕ2 adrenergic receptors, female gonadal hormones estrogen and progesterone, insulin, glucagon, elevated glucose levels and inter-compartmental redistribution - have all been shown to effectively reduce blood glutamate levels. Decreased blood glutamate concentration was associated with improved neurological outcome irrespective of the precise process which was involved in reducing glutamate concentration. Thus, the evolving role of blood glutamate levels in maintaining CNS glutamate homeostasis highlights the need to further characterize mechanisms involved in reducing blood glutamate. Keeping in mind the clinical applications of such modalities – these investigations should strive to identify those mechanisms which are least associated with adverse and toxic effects. To date, the promising results achieved with blood glutamate scavengers in animal models of brain insults, and the safety profile associated with these substances, warrants further studies in this field. This chapter concentrates on the physiologic, mechanistic and clinical roles of blood glutamate scavenging, particularly in the context of acute and chronic CNS injury. The authors discuss the details of brain to blood glutamate efflux, autoregulation mechanisms of blood glutamate, natural and exogenous blood glutamate scavenging systems, and redistribution of glutamate. They then propose different applied methodologies to reduce blood and brain’s glutamate concentrations and discuss the neuroprotective role of blood glutamate scavenging. Chapter 2 - Glutamate is the most abundant neurotransmitter in the human brain. There is growing evidence for the role of glutamate and dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia based on the findings of postmortem studies, studies of cerebrospinal fluid and psychomimetic effects of N-methyl-Daspartate (NMDA) subtype glutamate receptor antagonists. For decades, blockade of dopamine (D2) and serotonin (5-hydroxytryptamine, 5-HT2A) receptors has been playing the obligatory role in the actions of currently available antipsychotic drugs, which treat positive symptoms more effectively. However, the medical needs for negative and cognitive deficits remain unfulfilled. Recent studies have investigated the modulation of glutamatergic system, particularly the NMDA/glycine site, through genetic research and clinical trials by using a group of “NMDA-enhancing agents”. This chapter reviews the physiology of glutamate receptors, in particular the NMDA receptors, and its importance to the understanding of the pathophysiology of schizophrenia and future development of novel antipsychotics. Chapter 3 - Many pathological statements are accompanied by changing of blood sodium concentration with following fluctuation in extracellular osmolarity. That can happen surprisingly often. It is reported that hyponatremia is found in 1-2% all hospitalized patients. Changing of extracellular osmolarity leads to developing of hyperexcitability, seizures and coma with following damages of neurons. Molecular basis for this phenomenon is not clear.

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Preface

ix

Glutamate is main exciting neurotransmitter. It is shown that hypotonic swelling leads to a decrease of glutamate uptake in astrocytes and synaptosomes. This treatment also induces glutamate release from vesicular and cytosolic pool in neurons, astrocytes and synaptosomes. Except exocytosis, carrier reversal, specialised channels for instance maxi-anion channels and volume-sensitive outwardly rectifying anion channels (VSOR) are involved in glutamate efflux in hypotonic conditions. Hypertonic shrinking induces calcium-independent exocytosis in both neurons and synaptosomes. The authors suggest that these events can be basis for hyperexcitability in hypo- and hypernatremia. Pharmacological inhibiting of glutamate efflux pathway potentially can be used for treatment of neurological symptoms in case of blood osmolarity fluctuations. Chapter 4 - Glutamate has long been recognized as a major excitatory neurotransmitter in mammalian central nervous system (CNS) and is required for normal brain activities such as learning and memory. Its functions are mediated by glutamate receptors (Ionotropic and Metabotropic), transporters (present on the cell surface or in vesicles) and various other signaling molecules. Interestingly, glutamate receptors and/or transporters have also been found in several non-neuronal cell types, both inside and outside CNS. These include astrocytes in CNS and other tissues such as bone, heart, skin, gastrointestinal tract, pancreas, liver, lung, testis, adrenal/pituitary/pineal glands, megakaryocytes, platelets, thymocytes and lymphocytes. Functional glutamate signaling has been found in plants as well. Together, these suggest a more global role for glutamate as an extracellular signaling molecule involved in various physiological processes. However, although the physiological role for glutamate is well established in CNS, the same is not true for other non-neuronal cell types. This review summarizes the current knowledge on glutamatergic signaling in both neuronal and nonneuronal cell types with emphasis on chemoattraction. Chapter 5 - Prolonged treatment with CNS depressant drugs, such as the benzodiazepine anti-anxiety drugs increases the possibility of physical dependence manifested as withdrawal anxiety. While benzodiazepines have their anxiolytic, hypnotic and anticonvulsant actions via allosteric potentiation of GABA-A receptor function, during drug withdrawal modulation of excitatory – Į-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in hippocampal CA1 neurons is closely coupled to the expression of drug-withdrawal anxiety. Electrophysiological and immunochemical studies of rat CA1 neurons and minislices during withdrawal from 1-week oral flurazepam administration point to increased synaptic insertion of GluA1 homomeric AMPARs as a critical link in the behavioral expression of anxiety. The mechanism underlying drug-induced AMPAR potentiation during benzodiazepine withdrawal is analogous to electrical stimulus-induced long-term potentiation of hippocampal CA1 afferents, and involves a two-step process: insertion of GluA1 homomeric receptors followed by calcium-calmodulin kinase Type II (CaMKII)-mediated phosphorylation of Ser831GluA1 and enhanced estimated AMPAR single-channel conductance. Similar mechanisms of glutamatergic plasticity have also been observed in the nucleus accumbens following prolonged psychostimulant use, which may be involved in mediating the addictive properties of these drugs. Thus, CaMKII-mediated enhancement of GluA1 receptors is a highly conserved, final common signaling mechanism for normal physiological processes such as memory formation, as well as the pathophysiological development of physical dependence to drugs of abuse.

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Chapter 6 - Gamma-aminobutyric acid (GABA) and glutamate play critical roles in the mediation and modulation of nociception at peripheral, spinal and supraspinal levels. Supraspinally, these amino acid neurotransmitters, and their receptors, are present in key brain regions involved in the sensory-discriminative, affective and cognitive dimensions of pain perception. Modulation of central GABAergic and glutamatergic neurotransmission underlies both activation of the endogenous analgesic system and the therapeutic effects of a number of analgesics. Enhancement or suppression of firing of GABAergic and glutamatergic neurons, and associated changes in neurotransmitter release, have been reported in supraspinal sites associated with nociception in animal models of acute, inflammatory and neuropathic pain. Moreover, pharmacological modulation of central GABAergic and glutamatergic signaling results in altered nociceptive behaviour. Here the authors review recent evidence in this area. They consider how this research has enhanced our understanding of the neurochemical mechanisms underpinning nociception and discuss its implications for the development of novel analgesic agents. Chapter 7 - Kainate receptors (KARs), together with AMPA and NMDA, are typically described as ionotropic glutamate receptors. The functions of KARs have begun to be elucidated only in the last decade. While some the actions of KARs are classically ionotropic, surprisingly, others seem to involve the activation of second messenger cascades and invoke metabotropic roles for this type of glutamate receptor. In this chapter, they describe these metabotropic actions of KARs in relation to the putative signalling cascades involved. Although, it is still a mystery how KARs activate G-proteins to stimulate second messenger cascades, intriguingly in very recent studies, specific subunits of KARs have been demonstrated to associate with G-proteins. Altogether, the body of evidence supports the hypothesis that, together with the canonical ionotropic operation, KARs expedite long-lasting signalling by novel metabotropic modes of action.

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In: Glutamate: Functions, Regulation and Disorders Editors: Golda Chayat and Avital Yedidya

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Chapter 1

BLOOD GLUTAMATE SCAVENGING: INSIGHT INTO NEUROPROTECTION Alexander Zlotnik , Akiva Leibowitz and Matthew Boyko Department of Anesthesiology and Critical Care, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva, Israel

ABSTRACT

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Several acute brain insults such as stroke, traumatic brain injury, meningitis, subarachnoid hemorrhage, and chronic neurodegenerative states such as Alzheimer’s disease and amyotrophic lateral sclerosis , are characterized by a deleterious excess of glutamate in brain’s extracellular fluids. Excess of glutamate in brain interstitium, facilitates stimulation of glutamate receptors, which in turn lead to cell swelling, apoptosis and neuronal death, thus exacerbating neurological outcome. The classic approach, was aimed at antagonizing the astrocytic and glial glutamate receptors. While being a potentially promising in animal models, this approach has failed to demonstrate sound clinical benefit. An alternative approach to eliminating excess glutamate from brains interstitial fluids and CSF has been proposed, derived from the discovery of brain capillary endothelial glutamate transporters. A naturally-occurring brain-to blood glutamate efflux facilitated by a gradient driven transport across these transporters, has been shown to eliminate excess glutamate from brain fluids. Blood glutamate scavengers enhance this naturally occurring mechanism, increasing the rate at which excess glutamate is cleared. Reduction of blood glutamate concentration in plasma establishes a new, more favorable concentration gradient, facilitating transport of excess glutamate from brains’ extracellular fluids into the blood. Numerous studies demonstrate a strong correlation between blood glutamate concentrations and the concentration in the brain’s extracellular fluid, thus suggesting that blood glutamate concentration might significantly affect glutamate concentration in brain.

Corresponding author: Alexander Zlotnik MD, PhD. Director,Research Unit, Department of Anesthesiology and Critical Care, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva, Israel, 98105. Tel.: (972)-86400262, Fax: (972)-86403795.E-mail: [email protected]

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Alexander Zlotnik, Akiva Leibowitz and Matthew Boyko Recent studies have validated the effectiveness of the glutamate-scavenging approach in treatment of acute brain insults. Lower blood glutamate concentrations have been associated with improved neurological outcomes in both animal models and human studies. Conversely, elevated blood glutamate levels were associated with worse neurological outcomes. These findings lead to the notion that reducing elevated blood glutamate levels may play an important role in neuroprotection. One of the proposed blood glutamate reduction mechanisms introduced initially, involved the metabolism of glutamate into Į-ketoglutarate. This naturally occurring enzymatic process is mediated by activation of resident plasma enzymes glutamateoxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) in the presence of their respective co-enzymes oxaloacetate and pyruvate. Further studies, based on blood glutamate reducing modalities other than oxaloacetate and pyruvate, have shown that additional mechanisms may be involved as well. These mechanisms share common physiological processes regulating blood glutamate levels. Acute stress response mediated via activation of ȕ2 adrenergic receptors, female gonadal hormones estrogen and progesterone, insulin, glucagon, elevated glucose levels and inter-compartmental redistribution - have all been shown to effectively reduce blood glutamate levels. Decreased blood glutamate concentration was associated with improved neurological outcome irrespective of the precise process which was involved in reducing glutamate concentration. Thus, the evolving role of blood glutamate levels in maintaining CNS glutamate homeostasis highlights the need to further characterize mechanisms involved in reducing blood glutamate. Keeping in mind the clinical applications of such modalities – these investigations should strive to identify those mechanisms which are least associated with adverse and toxic effects. To date, the promising results achieved with blood glutamate scavengers in animal models of brain insults, and the safety profile associated with these substances, warrants further studies in this field. This chapter concentrates on the physiologic, mechanistic and clinical roles of blood glutamate scavenging, particularly in the context of acute and chronic CNS injury. We discuss the details of brain to blood glutamate efflux, autoregulation mechanisms of blood glutamate, natural and exogenous blood glutamate scavenging systems, and redistribution of glutamate. We then propose different applied methodologies to reduce blood and brain’s glutamate concentrations and discuss the neuroprotective role of blood glutamate scavenging.

INTRODUCTION Glutamate is known to act as an excitatory neurotransmitter in the central nervous system (CNS). Glutamate is a non-essential amino acid, and is the most abundant free amino acid in the CNS, accounting for approximately 60 percent of total neurotransmitter activity in the brain. Glutamate has several important roles in the development and function of normal brain activities, amongst them: A key regulator in the communication process between neurons1, development of plasticity in CNS 2, 3, and functioning as a fuel reserve1. Activation of NMDA receptors by glutamate is vital for brain function. They are central to many of the activitydependent changes in synaptic strength and connectivity that are thought to underlie the formation of memory and learning. There is growing evidence that physiological levels of synaptic NMDA receptor activation promote survival of many types of neurons or render them more resistant to trauma4. The beneficial effects of glutamate are greatly dependent on strict homeostasis, maintaining brain extracellular fluid (ECF) glutamate at concentrations

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Blood Glutamate Scavenging: Insight into Neuroprotection

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below their toxic range. Concentration of glutamate in brain’s ECF is very low, ranging between 0.3 and 2 μM/l1. This low glutamate concentration, is maintained by a wellestablished mechanism of compartmentalization of glutamate. Glutamate is stored in neurons within vesicles and is released into synaptic cleft when the neuron is depolarized. Glutamate released from neurons as a neurotransmitter stimulates glutaminergic receptors (ionotropic NMDA and AMPA or metabotropic glutamate receptors). Excessive stimulation of glutamate receptors is associated with neurotoxicity. Activation of ionotropic receptors by glutamate leads to opening of receptor-coupled ionophores in which calcium channels are of particular importance. Non-limited efflux of calcium into neurons, activating in turn plasmatic proteolytic enzymes, eventually results in neuronal death via apoptosis or necrosis [1, 5, 6]. Glutamate induced excitotoxicity is prevented by several mechanisms, precluding dangerous accumulation of free glutamate in brain ECF. These mechanisms include a large family of Na+ dependent glutamate transporters known as excitatory amino acid transporters (EAATs). EAATs are localized on cell membranes of neurons, astrocytes as well as endothelium of brain-blood barrier (BBB) [1, 6]. Glutamate released as a transmitter at the synapse is taken up by surrounding astrocytes and amidated to glutamine, a non-neuroexcitatory amino acid, which is then transferred back to neurons to be converted back to glutamate [7, 8]. However, other mechanisms exist as well. Glutamate has been found to move from brain into blood unidirectionally, a process facilitated by the presence of glutamate transporters on the abluminal membrane of brain endothelial cells. These glutamate transporters include: EAAT1, EAAT2 and EAAT3, which perform a high affinity, sodium-dependent glutamate transport into the endothelial cells [9-11]. They also harbor glutamine transporters that take up glutamine at the abluminal side of the membrane. In endothelial cells, glutamine is transformed into glutamate via glutaminase, resulting in glutamate build up, eventually reaching an endothelial cell concentration which is much higher than that of plasma. Glutamate is then transported into blood via facilitated diffusion, down an electrochemical gradient, reaching an average blood plasma concentration of 40 μM/L. This mechanism principally allows the efflux of glutamate from brain-to-blood despite the very unfavorable brain-to-blood glutamate concentration gradient. At the luminal membrane of endothelial cells, there is a low capacity glutamate carrier. The transport capacity for influx of glutamate from blood into brain is quite low, reaching > 80% saturation at normal plasma concentrations, resulting in a non-significant rate of glutamate influx into the brain [12, 13]. Despite their role in brain glutamate regulation, little attention has been given to the glutamate transporters present on brain blood vessels [14] and to their role in controlling brain extracellular glutamate. Although the brain-to-blood efflux of glutamate was discovered nearly 50 years ago [15], it has been widely ignored as an important glutamate removal mechanism. Recently however, the significant capacity of brain-to-blood glutamate efflux has gained renewed interest. In rats, glutamate artificially injected into cerebrospinal fluid is removed within a relatively short time period into the blood. 80% of radiolabeled glutamate injected into the cisterna magna was detected in rats’ peripheral blood within a few minutes after injection [16]. This phenomenon is attributed to the existence of the abluminal glutamate transporters, and the highly vascularized nature the brain. The brain possesses an extensive network of capillary blood vessels. The average capillary-to-capillary distance is 19±4μm, each gram of brain tissue containing 900 meters of capillaries. Total capillary surface area reaches 12 m2, so that on average, nearly every neuron has its own capillary at a distance of 8-

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20 μm. This vascular network accounts for the proportionally high cerebral blood flow accounting for up to 20% of total cardiac output [17-19]. All together, these mechanisms offer an effective means for removal of excess of glutamate from the brain’s ECF to the blood in presence of EAATs. Many acute and chronic neurodegenerative disorders are associated with pathologically elevated ECF glutamate levels, as clearly shown in many animal models and human clinical studies. These disorders include stroke [20], traumatic brain injury (TBI) [21], intracerebral hemorrhage [22], meningitis brain hypoxia [23], amyotrophic lateral sclerosis (ALS)[24], glaucoma [25], HIV dementia [26], glioma [27] and many others. Prevention of glutamate induced neurotoxicity should potentially prevent neuronal death and improve neurological outcomes. Based on these assumptions, recent predominating research applies strategies for minimizing the toxic effects of glutamate in the context ischemic stroke and traumatic brain injury (TBI), providing neuroprotection, including: inhibiting glutamate synthesis, blocking its release from presynaptic terminals, antagonizing its actions on postsynaptic receptors, and accelerating its reuptake from the synaptic cleft. Glutamate receptor antagonists have been demonstrated to be highly effective in providing neuroprotection in animal models of ischemia [28]. However, clinical trials using NMDA receptor antagonists following stroke and TBI have not met the promise of the animal experiments, at the best failing to provide significant neurological improvement, and in some instances - proven to be harmful, deteriorating neurological outcomes and increasing mortality rate [29-31]. Several significant complications have been described and have been attributed to deleterious interference with physiological glutamate receptor function in normal brain tissue as well as in brain tissue threatened with ischemia-mediated damage including: premature death, cardiovascular problems and the development of psychoses [28]. As previously mentioned, glutamate, in normal concentrations is critical for normal neuronal function by activating NMDA receptor signaling and maintaining the integrity between neurons. NMDA receptor antagonists which do not discriminate between the different actions of the receptor interfere with both the negative and positive effects of this signaling [4, 31]. Moreover, glutamate transporters which reside in many extra cerebral peripheral tissues such as in the pancreas [32-36], play an important role in metabolic regulation of glutamate, and are affected by these antagonists. NMDA receptor antagonists could probably negatively affect metabolic processes in the whole body. The absence of effective treatment for multiple neurodegenerative conditions encouraged research for new treatment modalities, which would focus on elimination of the excess toxic glutamate only. Teichberg et al. postulated that excess of glutamate in brain’s ECF may be safely and effectively removed into the plasma via transporter systems described above [37, 38]. Under normal conditions plasma glutamate concentration is 5-100 μM/l1, whole blood its concentration is 150-300 μM/l [39, 40] and in brain’s ECF it is only 0.3-2 μM/l. In order to remove excess glutamate from the brain to the blood the system must work against large concentration gradients. Decreasing the plasma/blood glutamate concentration should decrease this gradient and facilitate efflux of glutamate from the brain into the blood. This proposed neuroprotection mechanism, based on exaggerated efflux of glutamate from the brain to the blood utilizing the decrease of blood glutamate levels was termed “Neuroprotection by blood glutamate scavenging”. Compounds capable of reducing blood glutamate levels are designated “blood glutamate scavengers”. In contrast to NMDA receptor antagonists, blood glutamate scavengers do not affect the glutamate receptors or glutamate-

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Blood Glutamate Scavenging: Insight into Neuroprotection

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mediated synaptic activity. The scavengers eliminate only the pathologically elevated levels of glutamate in brain fluids. The activity of blood glutamate scavengers in stimulating brainto blood glutamate efflux is self-limiting, since the process slows down and stops when the excess glutamate levels have decreased to concentrations below the threshold of activation of the brain vasculature glutamate transporters (i.e below their Km values) which mediate the glutamate efflux into blood. Thus, blood glutamate scavengers will preserve the physiological effects of glutamate in regulating the metabolic and electrolyte balance, maintaining the neuronal integrity and exerting beneficial effects in neuro-repair after brain injury [41]. This mechanism of decreasing brain glutamate levels, maintains a balance between eliminating the undesirable effects of excess glutamate, while preserving its positive effects that are necessary to sustain life. This approach seems to be more important under pathological conditions for several reasons. First, after TBI, stroke and other neurodegenerative disorders BBB is disrupted, enabling free movement of glutamate between plasma and ECF, following it’s concentration gradient [25, 42]. Second, these pathologic conditions are associated with a several hundredfold elevation of glutamate concentration in brain’s ECF. The combination of these two factors makes the efflux of excess glutamate from the brain particularly sensitive to lower concentrations of glutamate. Third, plasma has a much more significant volume of distribution compared to brain’s ECF. In turn, consistent uptake of glutamate from plasma by skeletal muscle and splanchnic organs and ongoing metabolism of glutamate in the Krebs cycle, makes plasma capacity for glutamate almost unlimited [43].

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EVIDENCE SUPPORTING THE RELATIONSHIP BETWEEN BLOOD/PLASMA AND ECF GLUTAMATE LEVELS Berl et al. (1961) [15] were the first to show the existence of a brain-to-blood glutamate efflux following intracisternal administration of [14C]-glutamate. Within 1 minute, 25% of the injected [14C]-glutamate was found in plasma. This was later confirmed by Davson et al. [44] and by Al-Sarraf et al. [45] who, using a 90 min long ventriculo-cisternal perfusion of [14C]glutamate, recovered 55% of the radioactivity in blood and 17% in the brain parenchyma. Gottlieb at al. showed that a rapid brain-to-blood glutamate efflux indeed takes place since one observes radioactive glutamate appearing in blood as soon as it is injected into rat brain lateral ventricles. Authors further showed that this brain-to-blood glutamate efflux can be accelerated by the creation of a larger glutamate concentration gradient between the cerebrospinal fluid/capillary endothelial cell and blood plasma. Using two paradigms based on the fate of radiolabeled glutamate infused into brain, authors observed its increased appearance in blood and enhanced disappearance from brain following a decrease of blood glutamate levels16. These results were later confirmed using dual-probe brain microdialysis demonstrating increased elimination of excess glutamate from the brain parenchyma following intravenous administration of blood glutamate scavengers, and a decreased elimination following intravenous administration of glutamate, to artificially increase the blood glutamate concentration [38]. Campos and colleagues, using functional magnetic resonance imaging (MRI) in rat model of stroke showed that decrease of plasma glutamate levels with blood glutamate scavengers was associated with significant decrease of glutamate

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in the brain [46]. Both parameters were in close correlation with neurological improvement. Abu Fanne and colleges reported reducing of glutamate concentration in plasma was associated with decrease of glutamate in CSF after MCAO in rats [47] and after TBI in mouse [48]. This effect was evident irrespective of the way in which blood glutamate was eliminated (oxaloacetate, insulin, glucagon). Boyko et al. found that in a rat model of subarachnoid hemorrhage (SAH), administration of blood glutamate scavengers was associated with lower glutamate levels in CSF at 24h after onset of SAH (unpublished data). In human neurosurgical patients close correlation was found between glutamate concentrations in plasma and CSF [49]. Alfredson et al. found close correlation between plasma and CSF glutamate concentrations in healthy human volunteers [50]. Close correlation was found between plasma and CSF levels in different neurodegenerative disorders including stroke, HIV dementia [26, 51], migraine [25]. In human stroke, Castillo et al. showed that lower plasma glutamate levels correlated with lower concentrations of glutamate in patients cerebrospinal fluid (CSF) [20, 52]. Nevertheless, some studies are not capable of demonstrating a correlation between plasma and CSF/ECF glutamate levels [53]. However, in the last study methodological problems could contribute to this discrepancy (functional MRI and collection of plasma samples within a one week interval). Investigating plasma glutamate in TBI patients VuilleDit-Bille revealed that in late course of TBI, plasma glutamate levels were significantly elevated in venous blood collected from jugular bulb catheter (and therefore reflecting concentration of glutamate in blood drained from the brain) compared to glutamate concentration in systemic arterial circulation. This feature probably may be a reflection of continuous brain-to-blood glutamate efflux [54]. Although this difference did not reach statistical significance, it is not surprising, considering higher blood capacity of continuously moving blood. In summary, analysis of the literature available to date supports the conclusion that there is a strong correlation between plasma/blood and ECF/CSF glutamate concentrations in animals and humans, in healthy volunteers and in patients suffering from different neurodegenerative disorders. Blood glutamate concentrations may affect brain’s glutamate concentrations; therefore, reducing blood glutamate concentrations with blood glutamate scavengers may facilitate brain-to-blood glutamate efflux and in this way limit neurotoxic effects of glutamate.

EFFECT OF BLOOD GLUTAMATE LEVELS ON NEUROLOGICAL OUTCOME AND THEIR ASSOCIATION WITH DIFFERENT NEURODEGENERATIVE DISORDERS A large body of evidence supports the idea that elevated blood/plasma glutamate levels can exacerbate a course of many neurodegenerative conditions. Moreover, in some cases when neurodegenerative conditions are accompanied by elevated glutamate levels, elevated glutamate itself may be not a sequence of the neurodegenerative condition, but rather an etiological factor. Extensive data reveals a relationship between blood glutamate levels and different neurodegenerative conditions;

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1. TBI: oxaloacetate, pyruvate, GOT and GPT have been shown to significantly improve neurological outcome in rat model of TBI in close correlation with low blood glutamate levels [38, 55-59]. In contrary, artificial elevation of blood glutamate concentration deteriorated neurological outcome [55, 57]. Investigating plasma glutamate in TBI patients Vuille-DitBille revealed that in late phases of TBI, plasma glutamate levels were significantly elevated in venous blood collected from jugular bulb catheter compared to glutamate concentration in arterial blood [54]. Unfortunately, authors did not compare blood glutamate levels in TBI patients to healthy controls. Another study revealed a significant elevation of plasma glutamate levels in both arterial and jugular bulb blood samples during first 24 hours after TBI compared to healthy controls [42]. Unfortunately, authors did not evaluate the effects of elevated plasma glutamate levels on neurological outcome. 2. Stroke: In rat’s model of permanent middle cerebral artery occlusion (MCAO), neurological outcome correlated closely with blood [60] or plasma [46] glutamate levels. Puig et al. described pattern of plasma glutamate levels change in rats submitted to MCAO. They observed a 3-fold increase of plasma glutamate compared to baseline values. The onset of this amino acid increase began 4–6 h after ischemic induction, reached peak values at 8–24 h and returned to pre-ischemic values by 48–72 h [61]. In stroke, human plasma glutamate levels during the first 24 hours were shown to be in close correlation with volume of ischemic lesion on CT scan or MRI and neurological outcome [20, 52, 62, 63]. 3. Chronic renal failure (CRF): Plasma and whole blood glutamate levels have been shown to be significantly elevated in patients with CRF [64-66]. Insulin like growth factor binding protein (IGFBP) is elevated in patients with end stage renal failure, resulting in reduced bioactivity of insulin like growth factor (IGF-1) [67]. IGF-1 has been shown to significantly decrease blood glutamate levels. This effect is more pronounced in healthy patients compared to patients suffering from chronic renal failure (CRF) [67]. In contrary, elevated levels of IGFBP, promote elevation of plasma glutamate levels. CRF, which is known to be associated with elevated levels of IGFBP results in very high concentrations of glutamate in both plasma and whole blood of the patients with CRF. Glutamate concentrations are equally elevated in both plasma and RBC, and a plasma to RBC ratio 1:10 typical for healthy humans is preserved, while the concentration in skeletal muscle of CRF patients remains unchanged. The normal plasma to skeletal muscle glutamate ratio is 1:100 [67]. In post-absorptive conditions which include loss of body cell mass, glutamate has been shown to be the only amino acid which displayed a significant inverse correlation in muscle and RBC. In cancer patients, increased plasma glutamate levels were attributed to decreased capacity of peripheral skeletal muscle uptake [68]. Many patients with CRF develop dementia or uremic encephalopathy [69, 70]. It cannot be ruled out that elevated blood glutamate levels might significantly contribute to development of this condition, though firm support or contradiction to this suggestionis not readily available. 4. Depression: In several studies major depression in humans was associated with elevated blood glutamate levels compared to healthy controls [71-74]. Moreover, initiation of treatment with anti-depressants promoted decrease of blood glutamate levels, though not reaching normal values [72]. Involvement of glutaminergic a mechanism in pathogenesis of depression is additionally supported by the fact that NMDA receptor antagonists including ketamine, alleviate symptoms of depression. No attempts to decrease plasma glutamate levels for treatment of depression were undertaken [72].

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5. Dementia: In patients with HIV dementia plasma glutamate levels have been shown to be elevated compared to healthy volunteers matched according age and gender [26, 51]. Authors found a close correlation between clinical severity of dementia and elevated plasma glutamate levels [51]. 6. Schizophrenia: The data available in the literature about plasma glutamate levels in schizophrenic patients is inconsistent. There are few publications where authors found no difference in plasma glutamate levels between schizophrenic patients and controls. In those early studies the number of patients was only about 10 per group, and thus statistical power was insufficient to establish reproducibility and reliability for studies of schizophrenia [75]. Many authors reported later, that plasma glutamate levels were significantly higher in schizophrenic patients, especially neuroleptic resistant ones. Alfredsson et al. reported that plasma glutamate levels were increased correlating with clinical course from the acute to the remission stage [76]. Heijden et al. found that plasma glutamate levels were elevated in schizophrenic patients in correlation with severity of negative symptoms [77]. In animal model of schizophrenia induced with repeated administration of ketamine Tomia et al. found significant elevation of plasma glutamate while concentration of glutamate in CSF decreased significantly [78]. 7. Epilepsy: In the single study performed, no difference in plasma glutamate levels was found between 29 epileptic patients and control. However, administration of the antiepileptic drug lamotrigine revealed the role of glutamate in this condition. Such, patients that responded well on anticonvulsive therapy had significantly lover plasma glutamate levels than non-responders [79]. 8. Amyotrophic lateral sclerosis (ALS): Several studies showed association of this disorder with elevated blood glutamate levels. Iwasoki et al. found significant elevation of plasma glutamate levels in patients with ALS without correlation with severity of the disorder [80]. Andreadou et al. showed that plasma glutamate levels are significantly elevated only in spinal but not bulbar form ALS. The authors concluded that spinal and motor forms of ALS probably have different etiological and pathogenetic mechanisms. It deserves mention that authors found a relationship between extent of glutamate elevation and duration of the disease [24, 81]. 9. Migraine: Both plasma and SCF glutamate levels were found to be elevated compared to healthy controls in migraine [25]. Canazi et al. reported that plasma glutamate was elevated in patients suffering from migraine without aura. In patients suffering from migraine with aura, plasma glutamate levels did not differ from normal ones, but they had elevated concentration of glutamate in platelets [82]. In another study by the same group, plasma glutamate levels were elevated in patients suffering from both migraines with and without aura. Importantly, during headache periods glutamate was further elevated in patients with aura [83]. Ferrari and colleges reported that plasma glutamate levels were elevated in all the patients with migraine even between attacks and raised during headache episodes [84]. 10. Different: Plasma glutamate has been shown to be elevated in patients with rheumatoid arthritis with temparomandibular joint crepitus. Authors found direct correlation between blood glutamate levels and severity of temparomandibular joint resorption [85, 86]. Levels of glutamate in plasma were significantly elevated in patients with motor neuron disease [87]. Tominaga et al. reported elevated glutamate levels in patients with alcoholic liver disease, but not in non-alcoholic liver disease [88]. Iwasaki et al. found that in patients

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with Parkinson’s disease have elevated plasma glutamate levels, but did not find correlation between levels of glutamate and severity of the disease [80]. Glutamate levels were reported to be elevated in HIV positive patients. Authors found a positive correlation between plasma glutamate levels and amount of T4+ lymphocytes in patient’s blood. Importantly, initiation of the antiviral treatment with azydodeoxythymidine lead to decrease of plasma glutamate levels compared with non-treated patients [89]. Glutamate levels also have been reported to be elevated in gout. Authors concluded that elevated glutamate levels play an important role in pathogenesis of the disease [90]. In summary, elevated blood/plasma glutamate levels are associated with a plethora of neurodegenerative disorders, playing an important role in development and course of disease. Elevated plasma glutamate levels may increase concentrations of glutamate in brain ECF and in this way promote glutamate induced neurotoxicity, conversely it seems to be reasonable that decrease of plasma/blood glutamate levels should potentially have neuroprotective effect. As it follows from the discussion below, decreased blood glutamate concentration was associated with improved neurological outcome irrespective of the precise process which was involved in reducing glutamate concentration. These mechanisms share common physiological processes regulating blood glutamate levels. To date, several of them were established and reviewed below.

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DECREASING BLOOD GLUTAMATE LEVELS, AND CONTRIBUTETION TO NEUROPROTECTION? Blood glutamate levels are regulated by complex and poly-component mechanisms. Autoregulatory mechanisms are capable of maintaining relatively stable plasma glutamate levels in different circumstances, indicating the importance of maintaining stable glutamate concentrations in a relatively narrow range. Following, is a review of all mechanisms shown to effectively reduce blood glutamate levels.

1. Oxaloacetate, Pyruvate, GOT and GPT The central role in autoregulation of blood glutamate levels belongs to liver-delivered plasma resident enzymes glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) which in the presence of their co-substrates, oxaloacetate and pyruvate, respectively, convert glutamate into 2-ketoglutarate, aspartate and alanine respectively [16]. Gottlieb et al. showed in vitro that 1mM pyruvate was capable of decreasing glutamate levels by 30%, 1mM oxaloacetate by 40%, and their combination decreased glutamate as much as by 60% from baseline levels [16]. In vivo, the same scavengers decreased blood glutamate by 30-40% from baseline in naïve rats. The same compounds have been shown to effectively reduce blood glutamate levels in circumstances of different pathological conditions including TBI [55-57], stroke [46, 47, 60] Ability of blood glutamate scavengers to reduce blood glutamate levels was in close correlation with neurological outcome. Interestingly, blood glutamate scavenging activity has been shown to be dose related. When injected intravenously as a continuous infusion starting 60 min after TBI or stroke, during 30 min,

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oxaloacetate had a maximal effect in 1M solutions, gradually decreasing effect with lower doses until the effect disappeared at a dose of 0.01M [56]. Neuroprotective effects of oxaloacetate also correlated with higher doses and lower blood glutamate levels [56]. Pyruvate showed a similar dose-response pattern on blood glutamate levels. It’s blood glutamate reducing effect was maximal in dose of 1M solution, and decreased with decrease of dose and disappeared at dose 0.01 M [57]. However, it’s dose related neuroprotective effect relationship differed somewhat from oxaloacetate. In a model of stroke, the neuroprotective effect was maximal at 0.25M, thereof decreasing [60]. Previous studies have also suggested a U-shape dose-response curve for pyruvate, where pyruvate loses its efficacy at doses higher than 250mg/kg [91]. The discrepancy between oxaloacetate and pyruvate, leads to a conclusion that pyruvate induced neuroprotection is at least partially mediated via mechanism not related to blood glutamate scavenging activity [46, 57, 60]. The neuroprotective effects of oxaloacetate were extensively investigated in rat’s model of TBI. Oxaloacetate effectively improved short- and long-term neurological outcome after moderate-to-severe TBI. It significantly improved performance of motor and behavioral tests, reduced the extent of brain edema and improved survival of neurons in different regions of hippocampus [55, 56, 92]. The neuroprotective effect of oxaloacetate was in close correlation with extent of blood glutamate reducing effect. Pyruvate also has been shown effective treatment of both TBI and stroke. It significantly improved neurological outcome after stroke using motor and behavioral tests, reduced mortality rate, decreased BBB permeability and reduced size of lesion on brains’ histological examination (Boyko, Zlotnik et al. 2011). In TBI, pyruvate decreased an extent of brain edema, improved neurological outcome, and improved survival of neurons in different regions of hippocampus [56]. One may claim that oxaloacetate and pyruvate provide neuroprotection by other mechanisms such as acting directly on brain parenchyma rather than solely via a blood glutamate scavenging mechanism. Indeed, the neuroprotective role of oxaloacetate and pyruvate may be related to several additional mechanisms, including the activation of pyruvate dehydrogenase to restore cellular ATP levels, acting as a direct antioxidant, reacting with H2O2 to form water and carbon dioxide, the scavenging of hydroxyl radicals, the ability to stimulate NADPH-dependent peroxide scavenging systems, the inhibition of poly(ADPribose) polymerase activity, and the capacity to serve as an alternative source of energy thereby improving the brain’s energetic and redox status [93-96]. We extensively investigated this question, and there are several important findings supporting the glutamate scavenging neuroprotective mechanism. Several rather compelling arguments, however, can be raised to support the contention that oxaloacetate and pyruvate exert its neuroprotective effects mainly via blood glutamate scavenging. a) The oxaloacetate or pyruvate-induced neurological recovery after TBI is not observed in rats treated with combination of oxaloacetate and glutamate or pyruvate and glutamate. This finding is in line with the view that the presence of excess glutamate in blood prevents oxaloacetate or pyruvate to effectively exert its blood glutamate scavenging action which is necessary for a therapeutic enhanced efflux of excess glutamate from brain into blood. Were oxaloacetate and pyruvate to exert their therapeutic effect in the brain itself, it is not clear why this action would be prevented by intravenous excess of glutamate since the entrance of oxaloacetate or pyruvate first from blood into the brain and then further into neurons takes place via dicarboxylate transporters such as the NaDC-3 which are not inhibited by glutamate

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[97, 98]. One can further argue that the glutamate induced neutralization of the therapeutic effect of oxaloacetate or pyruvate must be exerted within the blood and not within the brain since glutamate does not significantly penetrate from blood into brain neither in normal physiological conditions [99] nor after the breakdown of the blood brain barrier [100]. b) The oxaloacetate and pyruvate-induced neurological recovery after TBI takes place following the administration of oxaloacetate or pyruvate within the time frame of elevated glutamate in brain, i.e up to 2 hours post TBI. Though the kinetics of brain glutamate elevation after TB were not meaasured, numerous studies demonstrate that the excess glutamate in rat brain fluid does not last more than 2 hours following either TBI or stroke [101-105 106] . Assuming that oxaloacetate or pyruvate therapeutic action is unrelated to blood glutamate scavenging but rather to an improvement of mitochondrial energetics, the observation that oxaloacetate and pyruvate have no therapeutic effect when administered two hours after TBI cannot be easily reconciled with the observation that mitochondrial dysfunction is observed for several hours after TBI [107-109] c) Neurological recovery after TBI and stroke has been shown to be dependent on two related determinants: oxaloacetate + GOT and pyruvate + GPT. Since the negligible neurological recovery obtained with low doses of pyruvate (0.05 mmole/100 g rat weight) could be due to the presence of limiting amounts of blood resident GPT, causing (as expected from the Michaelis–Menten enzyme rate equation) very slow rates of blood glutamate scavenging, we investigated whether the doses of pyruvate which are devoid of neuroprotective activity could become neuroprotective following an increase of the blood GPT levels. To test the above prediction in vivo, we administered 60 μg porcine heart GPT/100 g rat (assuming a volume of distribution of about 7 ml blood/100 g) increasing thereby the basal blood levels of endogenous rat GPT from 47 ± 2 u/l to 883 ± 34 u/l. Neurological recovery of rats subjected to TBI and treated IV with 5 nmol/100 g pyruvate (i.e. at a dose which by itself has no detectable therapeutic effect and produces no decrease of blood Glu levels) is significantly increased by the administration of 60 μg GPT/100 g rat, suggesting the involvement of blood GPT and of its blood glutamate scavenging activity, in the neurological recovery. The fact that GPT alone causes a decrease of blood glutamate levels and is neuroprotective can be accounted to the fact that the endogenous blood pyruvate concentration is about 0.15 mM and close to the pyruvate/GPT Km value [57]. The similar phenomenon has been observed when pyruvate in subtherapeutic dose and GPT were used for treatment of stroke [60]. Oxaloacetate-induced glutamate scavenging and its neuroprotective effects has been also shown to be dependent on GOT concentration. As in the case of pyruvate/GPT, when oxaloacetate was administered in very low doses and did not exert any scavenging or neuroprotective properties in rat model of TBI, addition of 0.14 nmol recombinant GOT GOT/100 g rat completely restored glutamate scavenging and neuroprotective activity of oxaloacetate [55]. The observation that the neurological recovery after TBI and stroke depends on the presence in blood of both oxaloacetate and GOT is in line with two predictions: a) that neuroprotection can be achieved by oxaloacetate/GOT or pyruvate/GPT-mediated blood glutamate scavenging; b) that the rate of GOT or GPT-mediated blood glutamate scavenging via transamination will not change if the product of the oxaloacetate and GOT or pyruvate and GPT concentrations are kept constant i.e. that lowering the oxaloacetate concentration in the solution injected into blood can be compensated by increasing the GOT concentration in

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that solution. The tight therapeutic synergism between blood oxaloacetate and GOT as well as pyruvate and GPT is also difficult to reconcile with the suggestion of an intraparenchymal site of action, as oxaloacetate/GOT or pyruvate/GPT should be both translocated from blood into brain to exert beneficial effects. The respective kinetics of intraparenchymal entry of oxaloacetate (which is specifically transported via a dicarboxylate transporter) and GOT (which cannot gain access into the brain via an intact BBB) are probably incompatible with a synergy of action since the BBB opening that begins at the time of the trauma is transient, and lasts no more than 30 minutes [100] while GOT is administered after 60-90 min post trauma. d) The observation that the neurological recovery after TBI correlates with the decrease in blood glutamate levels is in line with the concept that blood glutamate scavenging enhances the efflux of excess glutamate from brain into blood and thereby provides neuroprotection. This strong correlation cannot be explained by an intraparenchymal site of action of oxaloacetate or pyruvate. Though we do not rule out the possibility that oxaloacetate and pyruvate exert some neuroprotective effects within the brain, we believe that the major therapeutic action of oxaloacetate and pyruvate is decisively linked to its blood glutamate scavenging activity. e) Administration of oxaloacetate in the presence of maleate, a GOT inhibitor, abolished the oxaloacetate-induced improvement in NSS as well as the oxaloacetate-induced decrease of blood glutamate concentration. If neuroprotective effect of oxaloacetate would be related to any mechanism different from blood glutamate scavenging, blockade of GOT with maleate could not prevent neuroprotection by oxaloacetate [56]. In contrast to rat models of stoke and TBI, treatment of humans with oxaloacetate potentially has serious limitations. The required dosage of oxaloacetate in humans, corresponding to that used in rats may be toxic. The average human has 5 liters of blood and the 1 ml solution that is likely to be injected to stroke patients should contain, as in rats, about 1 mMole of oxaloacetate. As this solution ought to be at a neutral pH, about 2 mMole NaOH are added to neutralize the acidity of oxaloacetate. Thus, the injected solution should be 103 mmole. 5000 = 5 M/l of Oxaloacetate and 10M/l NaCl which will obviously not be tolerated by the patient. Addition of GOT to the treatment solution shall significantly decrease blood glutamate levels without injection of very high doses of oxaloacetate according to Michaelis– Menten enzyme rate equation [111]. Furthermore, Campos et al. showed that neurological outcome based on modified Rankin scale score at 3 months after the stroke and lesion size on CT scan was in close correlation to two parameters: normal serum glutamate but high blood GOT levels (twice the normal values) at admission [63]. GOT but not GPT has been shown to predictive values regarding outcomes in several hundreds stroke victims [63, 112]. Considering the potential of GOT and GPT for treatment of brain insults the pharmacokinetic and pharmacodynamic properties of these enzymes have been recently studied in in naïve rats. Human GOT injected intravenously as a bolus at dose of 3 μg/100g of weight lead to rise of GOT concentration in plasma from 87±8 u/l to 835±62 u/l, gradually decreased and returned to nearly baseline values by 24 hours. Without addition of oxaloacetate, even ten-fold elevation of GOT in plasma had only minimal (about 15% from baseline) reducing effect on blood glutamate values reached maximal significance by 4 hours after the treatment. Doubling the dose of GOT lead to a rise of plasma GOT activity by 1560±160 u/l, returning to nearly baseline levels by 24 hours, and significantly decreasing blood glutamate levels by 40% reaching maximal effect at 4 h after the treatment.

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The pharmacokinetic and pharmacodynamicproperties of GPT were investigated in a similar fashion as GOT. At 3 μg/100g plasma, GPT activity increased from 69±9 IU/L to 865±71 IU/L and at 6 μg/100g it reached 1771±152 IU/L. In both tested cases GPT levels remained significantly elevated by 24 h. In both dose regimens, glutamate levels were similarly decreased significantly compared to baseline, with the maximal effect seen between 8 and 12 h after the treatment. Treatment with intravenous GOT is unlikely to carry unwanted pathological consequences. Plasma glutamate fluctuates by about 50% during the circadian cycle[113], most likely due to the accumulation of glutamate in brain fluids during intense neuronal activity or the REM phases of sleep. GOT, may transiently increase several hundred fold, such as in hepatitis, without any known squeal – transient or permanent. Concentration of GOT and GPT in human plasma differs significantly compared to rodents. GOT levels in plasma of healthy males was shown to be 24±4 IU/L [39] while in rat males it was about 5 fold higher-132±36 IU/L. The difference between human and rats’ GPT levels seems to be less pronounced 27±9 IU/L versus 59±12 IU/L (animal values taken from our unpublished data basing on 150 S-D male rats). This striking difference may partially explain the excellent blood glutamate scavenging capacity and be at least partially responsible for the better and more complete neurological recovery after TBI and stroke in animals.

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2. Stress and Activation of ß2 Adrenergic Receptors While investigating fluctuations of blood glutamate levels after TBI in rats, a spontaneous decrease of blood glutamate levels was noted, taking place between 60 and 120 min after infliction of TBI [55-58, 114]. Thomassen et al. reported a significant decrease in plasma glutamate in the initial six hours of myocardial infarction in humans. This decrease was accompanied by a long lasting elevation of alanine, the end product of glutamate biotransformation, reflecting accelerated breakdown of glutamate [115]. We reasoned that such decrease could be part of a stress response due to the activation of the hypothalamopituitary-adrenal pathway typically seen after TBI, stroke, SAH and myocardial infarction. Adrenaline and noradrenaline blood levels increase following TBI, and their circulatory levels can rise up to 500-fold and 100-fold respectively [116]. These may remain elevated in the circulation of brain-injured patients several days after injury [117]. This hypothesis was confirmed by demonstrating that pretreatment with propranolol (a non-selective ȕ-antagonist) completely prevented stress-induced glutamate decrease and consequently spontaneous partial neurological improvement typically seen at 24-48 hrs after TBI. This data supports the important role of stress regulation of glutamate levels and again, importance of lower blood glutamate levels for neuroprotection [58, 59] In order to determine which of the components of the stress is responsible for glutamate-reducing effect, we treated naïve rats with either adrenaline, noradrenaline, corticotrophin releasing factor (CRF), adrenocorticotrophic hormone (ACTH) or cortisol [58]. While ACTH had no effect on blood glutamate, CRF significantly and consistently decreased blood glutamate levels. Antalarmine, (a selective type-1 CRF receptor antagonist) occludes the CRF-mediated decrease in blood glutamate levels. Investigating the effectors of the sympathetic/adrenomedullary system, we observed that in naïve rats, adrenaline but not noradrenaline decreased blood glutamate levels. Confirming the role of adrenaline, propranolol pretreatment (a non-selective ȕ-antagonist)

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prevented the spontaneous decrease of blood glutamate observed post TBI. We further observed that isoproterenol (a ȕ1, 2-selective adrenoreceptor agonist) produced a marked sustained decrease in blood glutamate levels. These results suggest that stress induces a decrease of blood glutamate levels partly via the activation of peripheral CRF receptors and the activation of the ȕ-adrenoreceptors [58]. To determine a kind of ȕ adrenergic receptors is responsible for blood glutamate reducing effect we additionally examined the effects of the activation of ȕ1 and ȕ2-adrenergic receptors on glutamate homeostasis in the blood of naïve rats and in rats submitted for TBI [114]. Using combination of different non-selective and selective ȕ adrenergic agonists and antagonists we showed that activation of ȕ2 receptors plays an important role in the homeostasis of glutamate, decreasing its levels in rat blood andpromoting neuroprotection. Conversely, activation of ȕ1 adrenergic receptors causes moderate elevation of glutamate in blood [39, 59, 118] Although role of ȕ2 adrenergic receptors in reducing blood glutamate concentration was well established, the precise mechanism by which ȕ2 receptors cause this effect remains unclear. At least two possible mechanisms may be involved. First, redistribution of unchanged glutamate may be enhanced from the blood into peripheral tissues, such as skeletal muscle, gut and liver. Those tissues have been shown to be responsible for absorption within 10 min for as much as 90 percent of glutamate injected into bloodstream as showed with radiolabeled glutamate and aspartate43. Concomitant infusion of adrenaline facilitated efflux of glutamate from the blood into skeletal muscle (unpublished data), and therefore release of adrenaline after TBI could contribute to elimination of glutamate from the blood. The second mechanism may be due to activation of endogenous GOT and GPT resulted from stress response and eventually leading to conversion of glutamate into 2-ketoglutarate, alanine and aspartate. It has been shown previously that stress increases activity of GOT and GPT in rats [119]. Different kinds of stress universally decrease blood glutamate levels. We observed such a decrease with stress induced by TBI, stroke, exposure to cold, perioperative stress after craniotomy with insertion of microdialysis probe and laparotomy (our unpublished data). Stress after injury is known to activate an adaptive response, which allows the body to marshal its forces to confront a threat and provide protection. Although a late surge of catecholamines may be detrimental [120], we propose that the stress-related release of adrenaline might serve to reduce brain injury by limiting the increase of glutamate in the brain’s fluids after head injury.

3. Insulin and Glucagon Effect of insulin and glucagon on amino acids and glucose metabolism was studied extensively. Aoki et al. showed on healthy volunteers that insulin increases uptake of glutamate into muscle [121]. Authors measured glutamate concentrations separately in plasma and whole blood and showed that insulin had very limited effect on glutamate concentration in plasma, but a significantly reduced glutamate concentration in whole blood. This effect could be explained by concomitant shift of glutamate from red blood cells (RBC), as an attempt to maintain stable concentration of glutamate in plasma while plasma-to-muscle glutamate shift takes place [121]. Leweling and colleges found that plasma glutamate levels are decreased in patients suffering from hepatic failure with hyperammoniemia.

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Hyperammoniemia is known to be a potent activator of insulin secretion and those patients have hyperinsulinemia. Authors suggested that lower glutamate levels seen in patients with hepatic failure are a sequence of hyperinsulinemia. Alanine (a metabolite of glutamate breakdown) is also decreased in those patients, suggesting that glutamate is decreased not a result of its metabolism, but rather as a result of its shift into skeletal muscle or slower synthesis of glutamate [122]. IGF-1 has been shown to significantly decrease blood glutamate levels. We investigated effect of insulin, glucagon and glucose in naïve rats [118]. Glucose, insulin and glucagon have all been shown to significantly reduce blood glutamate levels. Glucose induced glutamate reducing effect is probably related to the stimulating effect of glucose on insulin secretion [123]. In turn, elevated insulin promotes inflow of glutamate from plasma into skeletal muscle [124]. In contrary, elevated glutamate probably initiates secretion of both insulin and glucagon as part of a positive feedback mechanism, returning glutamate toward normal values. Previous studies have shown that glutamate stimulates both glucagon [125, 126] and insulin release [124, 127-130] by acting on a glutamate receptor of the AMPA subtype in pancreas to lower glutamate back to normal levels. It has been further described that glutamate exerts a much weaker stimulation for the secretion of glucagon than to that of insulin [125]. Despite having similar glutamate-scavenging properties, insulin and glucagon exhibit different glutamate reducing patterns. Administration of insulin led to an immediate and transient decrease in blood glutamate levels, while glucagon led to a delayed but long-lasting decrease in blood glutamate levels. Abu Fanne et al. showed that both insulin and glucagon treatment effectively reduces plasma and CSF glutamate levels in rats submitted to MCAO and in this way improved neurological outcome [47]. Glucagon induced hyperglycemia did not exacerbate neurological outcome in this study, despite the controversial clinical and experimental data suggesting that hyperglycemia is associated with worse neurological outcome (although recent data does not support this notion) [131, 132]. The same group observed a significant neuroprotective effect (motor tests and significant reduction of lesion size) in mice treated with glucagon prior to or after TBI [48]. This neurological improvement correlated with lower plasma and CSF glutamate concentrations. Authors postulated that neuroprotective effects of both insulin and glucagon were due to their blood and ECF glutamate scavenging effect.

4. Estrogen and Progesterone The gonadal steroids estrogen (E) and progesterone (P) are known female sex hormones associated with several reproductive functions. There is substantial biologic evidence to support that E and P also play an important role on the development, growth, differentiation, maturation, and function of various tissues throughout the body, including the peripheral and central nervous system [133]. E and P have significant neuroprotective properties against various neurodegenerative conditions [134-137]. For instance, both E treatment [135, 138, 139] and pre-treatment [139143] have been effective in decreasing neurological damage caused MCAO. Ereplacement therapy has been found to reduce the incidence of Alzheimer’s disease in postmenopausal women [135, 144]. It has been suggested that P also has neuroprotective properties in both ischemic stroke [140] and TBI in rats [145-149]. Although E and P are have been described

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as neuroprotective agents, the exact mechanism of estrogen and progesterone induced neuroprotection has yet to be determined. We suggest that E and P at least partially, may mediate their neuroprotective properties via a glutamate-related mechanism. Several recent findings support this hypothesis. While studying factors potentially affecting blood glutamate levels in healthy human volunteers we noted that of all the factors examined (age, time elapsed from the last meal or drink, gender, daily physical activity, recent coffee consumption etc.) only female gender was associated with significantly lower blood glutamate levels [39]. Plasma GOT and GPT levels were significantly lower in females compared to males. Due to their role in blood glutamate scavenging, higher levels of GOT and GPT in the female population are expected when compared to the male population, in order to sustain lower levels of glutamate in blood. This contradiction may be settled if lower glutamate levels in women is understood as genetically determined rather than a GOT and GPT scavenging mechanism. Accepting this approach, the lower concentrations of GOT and GPT enzymes would be a result of reduced need to convert glutamate into 2-ketoglutarate. Another possible explanation may be that E and P promote higher concentrations of oxaloacetate and pyruvate in plasma, serving as co-enzymes for GOT and GPT respectively. In this scenario, as expected from the Michaelis-Menten enzyme rate equation, lower levels of GOT and GPT would be necessary to convert the same amount of glutamate into 2-ketoglutarate, sustaining lower concentrations of glutamate in women’s blood [55, 56]. Nevertheless the exact mechanisms by which E and P may mediate their blood glutamate reducing effect are not clear and additional studies are warranted. To date, there is very little evidence in the literature on the influence of sex differences on glutamate levels. It has been described by Stover and Kempski that following isoflurane anesthesia in neurosurgical procedures, glutamate concentrations are more prominently elevated in male patients than in females [49]. Baseline levels of glutamate were also found to be lower in female patients [49]. Furthermore, it has been shown that female patients suffering from ALS [24, 81] have significantly lower plasma glutamate concentrations than males. In patients with rheumatoid arthritis and temparomandibular joint crepitus, worse clinical course of the disease was in inverse correlation with estrogen levels [85]. Fernholm et al. reported that plasma and RBC glutamate levels were elevated in patients suffering from growth hormone deficiency. This elevation was noted in male but not in female patients [150]. The effect of plasma E and P levels on glutamate was evaluated along the course of female menstrual cycle [40]. Fluctuations of plasma E and P levels during the average 28-day menstrual cycle are predictable [151-157]. As the menstrual cycle begins, plasma E and P levels are very low [151, 157]. Plasma E levels begin to rise on the 5th or 6th day of the cycle, with maximum values seen a day or two before ovulation occurs on the 14th day [151, 157]. There is a sharp drop after 3 days of maximal levels, followed by a secondary rise in plasma E between days 18 and 24, decreasing again to its original level at the end of the cycle [151, 157]. Plasma P levels remain extremely low until levels begin to rise mid-cycle [151, 157]. Plasma P levels reach maximal values between days 19 and 24 of the cycle, when P levels begin to drop to its original value [151, 157]. As expected, even in the beginning of menstrual cycle, women had significantly lower blood glutamate levels compared to males, despite the fact that at this time point blood glutamate levels were at their maximum, coinciding with minimal plasma levels of E and P. Later during the cycle, gradual decreases in blood

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glutamate levels occurred coinciding with elevating plasma E and P levels. The third and fourth blood samples, which normally represent the period where the highest levels of E and P are seen, blood glutamate levels dropped to almost half the initial values seen at the start of the cycle. In another human study, we investigated whether blood glutamate levels are influenced by changes in P and E levels observed during normal pregnancy [158]. It is well known that levels of E and P increase exponentially during pregnancy. Elevation of female hormones lead to significant decrease of blood glutamate levels during the 2nd and 3rd trimesters of pregnancy compared to 1st trimester. Despite higher levels of estrogen and progesterone during the 3rd trimester compared with the 2nd trimester, blood glutamate was not reduced additionally in 3rd trimester compared with the 2nd trimester. With the achievement of its maximal capacity, additional elevations in E and P levels do not further reduce glutamate. P has been shown to have ŀ-shaped dose-response curve with good effect in doses 4-18 mg/kg and disappearance of this effect in higher and lower concentrations [147]. For this reason, with high concentrations of progesterone during the 3rd trimester, a less pronounced effect on blood glutamate reduction was observed. The effect of E on blood glutamate levels in TBI in rats. E was injected to male rats as pretreatment and treatment at 60 min after TBI. E lead to significant and sustained decrease of blood glutamate levels in all the groups correlating with improved neurological outcome, as it shown with improved motor-behavioral tests and decreased brain edema in rats treated with E compared to controls(Zlotnik, Leibowitz et al. 2011).

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5. Extracorporeal Methods of Glutamate Elimination In contrast to all the methods described above, extracorporeal (hemodialysis, hemofiltration) methods of glutamate elimination have several important advantages. First and foremost, those methods provide definitive elimination of excess of glutamate from different compartments, rather than redistribution or reversible conversion into glutamate metabolites. Second, considering that majority of pharmacological options listed above cannot be used for treatment of humans since they have not yet undergone the required safety trials, extracorporeal methods have been widely used in many conditions in ICU patients and therefore could be easily used in a new application for this purpose. Investigating metabolism of amino acids in patients with hepatic encephalopathy Koivasalo and colleges found that extracorporeal removing systems effectively remove many amino acids including glutamate, and improving amino acids profile toward normal one [159]. We suggest that similar extracorporeal removing systems may be usefully applied precisely for elimination of glutamate excess in different neurodegenerative conditions. There are several studies investigating loss of amino acids during hemodialysis in patients with end stage renal disease [64-66]. Among different amino acids that are removed with dialysate during hemodialysis was glutamate. We postulate that hemodialysis may be used specifically to remove glutamate from patient’s body to achieve neuroprotection. Glutamate, GOT and GPT concentrations were monitored during standard 4-hours long hemodialysis in patients with CRF. Blood glutamate was significantly decreased at all the time points during dialysis. GOT and GPT levels in blood decreased after dialysis. This study clearly showed that glutamate may be effectively eliminated during hemodialysis and its levels may be significantly reduced during at least 4 hours after beginning of the procedure.

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Thus, such an approach may be feasible for ICU patients suffering from stroke or TBI. Unfortunately, hemodialysis may have several limitations: First, a significant proportion of the patients admitted to ICU, suffer from hemodynamic instability, particularly hypovolemic, and septicshock. Second, anticoagulation is required for hemodialysis procedures in order to prevent clot formation in the set’s tubing. Anticoagulation may be detrimental for patients suffering from multiple trauma or isolated head injury because of risk of bleeding. In these circumstances continuous hemofiltration may be a preferable approach. Considering that diameter of pores in membranes of filter used for hemofiltration are larger than those used for hemodialysis, we postulated that hemofiltration may be a surrogate for hemodialysis when decrease of blood glutamate concentrations is desirable. Hemofiltration leads to lower incidence of hemodynamic instability and may be applied with only minimal anticoagulation. It is widely utilized in ICU patients in many conditions including acute renal failure, severe sepsis and septic shock, ARDS, hyperkalemia etc. Early initiation of extracorporeal removal of excess glutamate from the plasma may be a useful tool for treatment acute neurodegenerative conditions. Such a study is currently going on, results should be available promptly. Peritoneal dialysis resulted in a loss of 1.5 to 4.6 grams of amino acids in 24 hours [160, 161], whereas HD can lead to a loss of up to 8 grams of amino acids [162]. Based on those data, we postulated that peritoneal dialysis may be almost as effective as hemodialysis or hemofiltration for elimination of glutamate from the body. It does not require any anticoagulation cannot initiate hemodynamic instability, and may be safely used for a long period of the time requiring only a minimal surgical intervention, lasting less than 30 min under local anesthesia. Presently we have been studying this approach for effectiveness of glutamate elimination and determination of glutamate clearance in patients on chronic peritoneal dialysis.

6. Hypothermia Hypothermia has been implied as a treatment modality associated with improved neurological outcome following different neurological disorders including TBI, stroke, and global ischemia [163-171]. Several mechanisms were suggested to be involved in hypothermia induced neuroprotection. They include but not limited by decreased cerebral metabolic rate, decreased cerebral blood flow and lower intracranial pressure, limited free oxygen radicals formation, decrease of glutamate release in brain [172]. Recently we examined the effect of moderate hypothermia (30°-32° Celsius) on blood glutamate levels in naïve rats. Rats were exposed to external cooling under Isoflurane anesthesia during 6 consequent hours. This lead to a 40% reduction of glutamate, and lasted up to 9 hours. This process was accompanied by elevation of plasma GOT and GPT levels which may contribute to the decrease of blood glutamate levels via facilitated conversion of glutamate into 2ketoglutarate by those enzymes. Previously cold exposure was shown to lead to multifold elevation of plasma GOT and GPT activity in rats [119].

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7. Other Methods to Decrease Blood Glutamate Levels Stover showed that Isoflurane anesthesia after TBI in rats was associated with elevation of blood and CSF glutamate levels. Chloral hydrate partially prevented elevation of blood glutamate resulted from Isoflurane anesthesia [173]. Cristobal et al. reported that aspirin was capable of preventing elevation of blood glutamate levels caused by long-lasting immobilization test in rats [174-177]. Overall, there is a rich arsenal of tools that have been shown to decrease blood and ECF glutamate concentration in experimental setting. Unfortunately, almost none were tested in clinical setting, and such human clinical trials are warranted.

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FACTORS ELEVATING BLOOD GLUTAMATE LEVELS As previously discussed, elevated blood glutamate levels may interfere with normal brain-to-blood glutamate efflux and may therefore worsen neurological outcome in different neurological conditions [55-57, 173]. Thus, factors elevating blood glutamate levels should be avoided in the conditions where glutamate has been shown to exhibit its neurotoxic properties. Meals rich with monosodium glutamate have been shown to elevate circulating blood and muscle glutamate levels in both humans and animals [130, 178]. Interestingly, ingested glutamate increases plasma but not RBC concentration since glutamate is not transferred into RBC, but is rather formed in the RBC from glutamine by glutaminase [113]. Elevation of glutamate in muscle reflects very fast distribution of huge amount of ingested glutamate in attempt to quickly restore elevated blood glutamate levels toward normal range. Ordinary meals, not enriched with monosodium glutamate do not significantly influence blood or plasma glutamate levels due to very fast first pass metabolism in gut and liver [130]. Elevated aspartate concentration in this study reflected enhanced breakdown of glutamate. Physical exercise may be a powerful stimulus elevating glutamate concentration in the blood in both animals [179] and humans. Studies in athletes and laymen submitted to extreme physical exercise found a pattern of initial elevation of glutamate and alanine followed by a decrease in blood levels throughout the recovery process [180-183]. A recent study demonstrated that strong physical exercise led to a significant elevation in blood glutamate in healthy volunteers performing veloergometry for the duration of 60 minutes. Most likely this elevation resulted from skeletal muscle damage as it has been associated with elevated myoglobin and CPK levels. It leads to redistribution of glutamate from muscle into the circulation. Glutamate concentration in skeletal muscle has been shown to be 100 times higher than in plasma [67]. This may be of importance in clinical scenarios such a multitrauma, crush injuries, compartment syndrome, severe hyperthermia, heat stroke and rhabdomyolisis where extensive muscle damage may accompany brain injury. However, participants were capable of maintaining a stable blood glutamate concentration despite a continuous leak of fresh glutamate from the injured muscle, as levels returned to baseline values soon after the cessation of physical exercise. This finding reflects the importance of the body to maintain blood glutamate concentrations within normal physiological ranges. 2ketoglutarate was also found to be elevated for long periods of time, reflecting an ongoing process of glutamate breakdown. Lastly, elevated concentrations of GOT and GPT in plasma

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reflected the importance of these enzymes in the maintenance of stable blood glutamate concentrations. Severe hyperthermia was associated with multifold elevation of blood glutamate in rats submitted to severe hyperthermia by external heating. We postulated that this elevation was a heat mediated sequence of muscle injury [184]. This idea was supported by significant elevation of markers of muscular damage, myoglobin and CPK. In the circumstance of uncontrolled massive shift of glutamate from damaged muscle, blood glutamate scavengers oxaloacetate and pyruvate were ineffective in decreasing blood glutamate levels. It cannot be ruled out that worse neurological outcome associated with hyperthermia after brain insults may be at least partially determined by elevation of glutamate during hyperthermic events184. Selective stimulation of ȕ-1 adrenergic receptors has been shown to elevate blood glutamate levels in rats in contrary to ȕ-2 adrenergic receptors that were associated with blood glutamate reducing effect [58, 114]. Long lasting immobilization stress in rats has been shown to elevate plasma glutamate levels in rats [175]. Several hormones have been associated with elevation of plasma glutamate levels. Both hydrocortisone [58, 185] and thyroid [58, 185] hormones were shown to elevate plasma glutamate concentration in rats. In humans, hyperthyroidism also raises blood glutamate levels, but hypothyroidism has no blood glutamate reducing effect [185]. In patients with growth hormone deficiency blood glutamate levels were increased [150]. Stover and colleagues described elevation of glutamate levels in plasma during neurosurgical procedures, which was more pronounced in patients underwent the surgery under Isoflurane based anesthesia than under total intravenous anesthesia based on infusion of propofol and opiates [49]. The same authors observed a more significant elevation of plasma glutamate levels in rats submitted to TBI and exposed to Isoflurane anesthesia than in rats exposed to chloral hydrate based anesthesia [173].

COMPARTMENTAL MODEL OF GLUTAMATE DISTRIBUTIVE PROCESS IN THE BODY Glutamate molecules which leave the brain’s ECF may potentially be redistributed unchanged from compartment to compartment. This chain may be described as follows: Brain’s ECF-Æ Blood (including two relatively separated compartments plasma and blood cells)-Æ peripheral tissues, especially skeletal muscle and liver. In normal conditions, the glutamate concentration ratio between brain’s ECF, plasma, RBC and skeletal muscle may be described as 1:25:250:2500 respectively [1, 67]. In this pathway, glutamate transporters facilitate the passage of glutamate against concentration gradients. Certain conditions may modify this pathway [43]. For example, in normal brain’s ECF, glutamate concentration is only 0.3-2 μM/l, while just few minutes after brain insult it might increase hundreds fold. In this situation glutamate shift may become independent of glutamate transporters, and in case of BBB disruption may undergo passive diffusion. Conversely, membrane disruption as encountered in muscle injury may significantly influence glutamate transport and even reverse its direction [184]. Blood cannot be considered a single compartment, due to role of red blood cells in this context. RBCs serve as a glutamate depot in the body, and may accumulate glutamate when

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muscular mass, normally serving the main depot for glutamate, is decreased [67]. Platelets supposedly have an important role in glutamate distribution as well [62]. In vitro studies show that collagen induced activation of platelets, obtained from the blood of healthy volunteers, leads to release of large amounts of glutamate which was capable of increasing glutamate levels in plasma by 70%. In contrary, activation of platelets obtained from blood of stroke victims did not result in elevation of plasma glutamate. This is explained by platelet activation which occurs prior to blood sampling in stroke patients, so by the time of blood collection, glutamate stores in platelets have been already depleted in vivo. Authors concluded that activation of platelets and subsequent glutamate release is responsible for glutamate elevation typically seen in stroke patients [62]. This proposed mechanism seems to be more reasonable than that of simple shift of glutamate from brain’s ECF into blood, considering huge difference in volume of distribution between them, and multiple regulatory mechanisms existing in blood. Which is the ideal compartment for assessing glutamate levels, whole blood or plasma? remains unclear. Favorable glutamate concentrations may make the removal of excess glutamate possible. Birth asphyxia is a leading cause of neurological pathology and death in newborns [186]. Elevated glutamate concentrations in the brain’s extracellular fluids (ECF) are associated with a worse neurological outcome after fetal asphyxia. Following a hypoxic event, the activation of glutamatergic receptors initiates a cascade of events that results in cellular necrosis and apoptosis [186-188]. It is known that the placenta has an abundance of glutamate transporters, and is capable of removing of excess of glutamate by active transport from the fetal to maternal blood [189, 190]. Amino acid concentrations in the fetus are higher compared with maternal concentrations [190, 191]. The glycine-glutamate turnover cycle between the fetal circulation and placenta has been well described. Glycine is transported from the mother into the fetal circulation by active transport, and is converted to glutamate predominantly in fetal liver. When excess glutamate is present in the fetal circulation, the glutamate is transported to the placenta to prevent glutamate-induced neurotoxicity. The placenta is responsible for the metabolism of as much as 80 percent of fetal glutamate [189, 190]. Based on our prior studies with blood glutamate scavengers, we hypothesized that fetal blood glutamate concentrations may be reduced via a reduction of maternal blood glutamate levels. This decrease in fetal blood glutamate concentrations is expected to result in rapid transport of excess glutamate from the fetal brain to the blood, thereby providing neuroprotection. This is especially important because this provides the potential to begin early treatment in utero, with continuation of treatment after delivery. As the first step, we investigated glutamate concentration gradient between maternal blood and blood collected immediately after delivery from umbilical vein an artery. We demonstrated that glutamate concentrations in whole blood were twice as higher in both the umbilical arterial and venous blood compared with maternal blood. GOT levels were significantly higher in the umbilical arterial and venous plasma compared with maternal plasma, while GPT levels were not significantly different. The concentration of glutamate in fetal blood correlated with the glutamate concentration in maternal blood, supporting our suggestion of close relationship between them. It was previously shown that the concentrations of many amino acids in fetal plasma exceed the concentrations in maternal plasma [191]. The fetal liver actively converts glycine into glutamate, and elevated concentrations of glutamate are actively eliminated via the placenta to prevent glutamate-induced neurotoxicity [189, 190]. The glutamate transporters EAAT1, EAAT 2, and EAAT 3 are located in the placenta, and are key components of the

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glutamate-glutamine cycle responsible for glutamate transport across cell membranes [189]. The placenta also metabolizes up to 80 percent of glutamate taken up from the fetal circulation [189]. The elevated glutamate concentrations in fetal blood relative to maternal blood, as demonstrated in this study, may not be due to limited glutamate clearance. Rather, these higher concentrations more likely reflect the important role of glutamate for normal brain development. Excitatory amino acids were shown to be crucial in the development of brain plasticity in animals and humans, and the expression of glutamate receptors is enhanced in the developing animal and human brain. It has further been shown that plasma glutamate concentrations are maximally elevated in newborns, rapidly decrease during the first months of life, and then slowly decreases over the following several years [2, 3]. As such, NMDA receptor blockade significantly influences the development of cortical plasticity [192]. Our finding that the elevated concentration of GOT in fetal plasma directly correlates with the rise in glutamate suggests that the elimination of glutamate does not rely solely on the placenta. Rather, this elevation of GOT is likely necessary to maintain the adequate balance between the positive and negative effects of glutamate on the developing brain. Hays and colleagues showed that dietary glutamate is almost entirely removed from the bloodstream via first pass metabolism through the splanchnic bed in premature infants [193]. This is not surprising considering the very high concentrations of GOT in newborns' plasma, supporting the idea that the elevated GOT levels have high glutamate-converting capacity in the context of elevated blood glutamate levels. Conversely, GPT levels were not elevated in fetal plasma, suggesting that the GPT-dependent mechanism of glutamate metabolism plays a less significant role than GOT. The limited significance of GPT compared with GPT reflects previous observations in adult humans after ischemic stroke [46, 194-196] and in rats after TBI [57]. In this study, we demonstrated a strong positive correlation between maternal and fetal blood glutamate levels. This is an especially important finding because it suggests that one may possibly decrease fetal blood glutamate levels by decreasing maternal blood glutamate levels. This may allow for the initiation of treatment directed at decreasing glutamate concentration in the fetal brain, promoting neuroprotection without affecting the vitally important functions of glutamate in the developing brain. Considering that the placenta has a well-developed system of transporters for glutamate elimination, it seems plausible that one may create a favorable chain of glutamate concentration gradients that would ultimately lead to the elimination of excess glutamate from the fetal brain. This chain would start with the reduction of glutamate concentrations in the maternal blood compartment, thereby creating a favorable glutamate gradient between the maternal and fetal blood. This would lead to a placenta-mediated efflux of glutamate from the fetal to maternal blood. Decreases in fetal blood glutamate concentrations should then facilitate the efflux of excess of glutamate from the fetal brain’s ECF compartment, thereby preventing its neurotoxic effects. The results of this study may offer new therapeutic insights into fetal blood glutamate reduction in utero by way of reducing maternal glutamate levels.

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[39] Zlotnik A, Ohayon S, Gruenbaum BF, et al. Determination of factors affecting glutamate concentrations in the whole blood of healthy human volunteers. J. Neurosurg Anesthesiol. 2011;23: 45-9. [40] Zlotnik A, Gruenbaum BF, Mohar B, et al. The Effects of Estrogen and Progesterone on Blood Glutamate Levels: Evidence from Changes of Blood Glutamate Levels During the Menstrual Cycle in Women. Biol. Reprod. 2010;2010. [41] Biegon A, Fry PA, Paden CM, et al. Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc. Natl. Acad. Sci. USA 2004;101: 5117-22. [42] Suzuki M, Kudo A, Sugawara A, et al. Amino acid concentrations in the blood of the jugular vein and peripheral artery after traumatic brain injury: decreased release of glutamate into the jugular vein in the early phase. J. Neurotrauma 2002;19: 285-92. [43] Klin Y, Zlotnik A, Boyko M, et al. Distribution of radiolabeled l-glutamate and daspartate from blood into peripheral tissues in naive rats: significance for brain neuroprotection. Biochem. Biophys. Res. Commun 2010;399: 694-8. [44] Davson H, Hollingsworth JG, Carey MB, et al. Ventriculo-cisternal perfusion of twelve amino acids in the rabbit. J. Neurobiol. 1982;13: 293-318. [45] Al-Sarraf H, Preston JE, Segal MB. Acidic amino acid clearance from CSF in the neonatal versus adult rat using ventriculo-cisternal perfusion. J. Neurochem. 2000;74: 770-6. [46] Campos F, Sobrino T, Ramos-Cabrer P, et al. Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study. J. Cereb. Blood Flow Metab. 2011;31: 1378-86. [47] Abu Fanne R, Nassar T, Heyman SN, et al. Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate. Am. J. Physiol. Regul Integr Comp Physiol 2011. [48] Fanne RA, Nassar T, Mazuz A, et al. Neuroprotection by glucagon: role of gluconeogenesis. J. Neurosurg. 2010;114: 85-91. [49] Stover JF, Kempski OS. Anesthesia increases circulating glutamate in neurosurgical patients. Acta Neurochir. (Wien) 2005;147: 847-53. [50] Alfredsson G, Wiesel FA, Tylec A. Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers. Biol. Psychiatry 1988;23: 689-97. [51] Ferrarese C, Aliprandi A, Tremolizzo L, et al. Increased glutamate in CSF and plasma of patients with HIV dementia. Neurology 2001;57: 671-5. [52] Castillo J, Davalos A, Noya M. Progression of ischaemic stroke and excitotoxic aminoacids. The Lancet 1997;349: 79-83. [53] Shulman Y, Grant S, Seres P, et al. The relation between peripheral and central glutamate and glutamine in healthy male volunteers. J. Psychiatry Neurosci. 2006;31: 406-10. [54] Vuille-Dit-Bille RN, Ha-Huy R, Tanner M, et al. Changes in calculated arterio-jugular venous glutamate difference and SjvO2 in patients with severe traumatic brain injury. Minerva Anestesiol 2011. [55] Zlotnik A, Gurevich B, Tkachov S, et al. Brain neuroprotection by scavenging blood glutamate. Exp. Neurol. 2007;203: 213-20.

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[196] Campos F, Sobrino T, Ramos-Cabrer P, et al. High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke. J. Cereb. Blood Flow Metab. 2011. [197] Campos F, Sobrino T, Ramos-Cabrer P, et al. Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study. J. Cereb. Blood Flow. Metab. 2011.

Boyko, M., A. Zlotnik, et al. (2011). "Pyruvate's blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke." Eur J Neurosci 34(9): 1432-1441. In previous studies, we have shown that by increasing the brain-to-blood glutamate efflux upon scavenging blood glutamate with either oxaloacetate or pyruvate, one achieves highly significant neuroprotection particularly in the context of traumatic brain injury. The current study examines, for the first time, how the blood glutamate scavenging properties of glutamate-pyruvate transaminase (GPT), alone or in combination with pyruvate, may contribute to the spectrum of its neuroprotective mechanisms and improve the outcome of rats exposed to brain ischemia, as they do after head trauma. Rats that were exposed to permanent middle cerebral artery occlusion (MCAO) and treated with intravenous 250 mg/kg pyruvate had a smaller volume of infarction and reduced brain edema, resulting in an improved neurological outcome and reduced mortality compared to control rats treated with saline. Intravenous pyruvate at the low dose of 31.3 mg/kg did not demonstrate any neuroprotection. However, when combined with 0.6 mg/kg of GPT there was a similar neuroprotection observed as seen with pyruvate at 250 mg/kg. Animals treated with 1.69 g/kg glutamate had a worse neurological outcome and a larger extent of brain edema. The decrease in mortality, infarcted brain volume and edema, as well as the improved neurological outcome following MCAO, was correlated with a decrease in blood glutamate levels. We therefore suggest that the blood glutamate scavenging activity of GPT and pyruvate contributes to the spectrum of their neuroprotective mechanisms and may serve as a new neuroprotective strategy for the treatment of ischemic stroke. Zlotnik, A., A. Leibowitz, et al. (2011). "Effect of estrogens on blood glutamate levels in relation to neurological outcome after TBI in male rats." Intensive Care Medicine.

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Chapter 2

GLUTAMATE AND SCHIZOPHRENIA Huey-Jen Chang,1,2 Hsien-Yuan Lane1,3 and Guochuan E. Tsai4, 1

Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 2 Department of Psychiatry, Taichung Veterans General Hospital, Chiayi and Wanqiao Branch, Chiayi, Taiwan 3 Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan 4 Department of Psychiatry, Harbor-UCLA Medical Center, U. S.

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ABSTRACT Glutamate is the most abundant neurotransmitter in the human brain. There is growing evidence for the role of glutamate and dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia based on the findings of postmortem studies, studies of cerebrospinal fluid and psychomimetic effects of Nmethyl-D-aspartate (NMDA) subtype glutamate receptor antagonists. For decades, blockade of dopamine (D2) and serotonin (5-hydroxytryptamine, 5-HT2A) receptors has been playing the obligatory role in the actions of currently available antipsychotic drugs, which treat positive symptoms more effectively. However, the medical needs for negative and cognitive deficits remain unfulfilled. Recent studies have investigated the modulation of glutamatergic system, particularly the NMDA/glycine site, through genetic research and clinical trials by using a group of “NMDA-enhancing agents”. This chapter reviews the physiology of glutamate receptors, in particular the NMDA receptors, and its importance to the understanding of the pathophysiology of schizophrenia and future development of novel antipsychotics.

Correspondence: Guochuan Emil Tsai, MD, PhD. Department of Psychiatry, Harbor-UCLA Medical Center, 1000 W. Carson Street, Torrance, CA 90509, USA. Tel.: +1 310 781 1401; fax: +1 310 781 1093. E-mail address: [email protected].

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1. INTRODUCTION Glutamate is an excitatory neurotransmitter that plays a central role in nitrogen metabolism and participates in multiple biochemical pathways. About 60 % of all excitatory synapses in the central nervous system are stimulated by the neurotransmitter, glutamate (Nieuwenhuys 1994). During normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft after being released from presynaptic terminals in response to neuronal depolarization, which is rapidly decreased in the lapse of milliseconds while being cleared from the synaptic cleft through uptake by neuronal or glial glutamate transporters, where it is converted to glutamine, transported back to the presynaptic neuron, and reconverted to glutamate (Clements et al., 1992; Rothstein et al., 1994; Amara and Fontana, 2002; Rothman et al., 2003; Hashimoto et al., 2005) (Figure 1). Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate (Shulman et al., 2003). The regulation of the release and re-uptake of the excitatory neurotransmitter glutamate is critical for mammalian brain function (Erecinska and Silver, 1990), and that dysregulation of glutamate-glutamine cycle may be implicated in the pathophysiology of schizophrenia (Olney and Farber, 1995; Goff and Coyle, 2001; Coyle and Schwarcz, 2000; Hashimoto et al., 2004, 2005). In addition, glutamate plays an important role in synaptic plasticity via the interaction with a specific type of glutamate receptor, N-methyl-D-aspartate receptor (NMDAR), and is involved in most aspects of normal brain function including cognition, memory and learning (McEntee and Crook, 1993; Sapolsky 2005). Schizophrenia is a heterogeneous disorder, with patients showing substantial variability in symptom expression, psychosocial functioning, and intellectual impairment, which are categorized as three core symptom domains: positive symptoms, negative symptoms, and neurocognitive deficits (Keefe et al., 1999; Heaton et al., 2001). Positive symptoms may fluctuate during the course of the illness, but negative symptoms and cognitive dysfunction remain relatively constant (Tamminga et al., 1998). Each of these symptoms contributes to the morbidity of the illness, leading to various functional impairments, such as performance of independent living skills, social functioning, and occupational/educational performance and attainment. Negative symptoms and neurocognitive deficits, in particular, account for much of the long-term morbidity and poor functional outcome (Green 1996; Weinberger and Gallhofer, 1997; Velligan et al., 1997; Kirkpatrick 2001; Milev et al., 2005; Lysaker and Davis, 2005). Thus, negative symptoms and neurocognitive deficits have become a target for novel therapy (Green 1996; Sharma and Antonova, 2003). For decades, pathophysiological investigations of schizophrenia have mainly focused on the dopaminergic and serotonergic systems (Matthysse 1973; Weinberger 1987), however, there is growing evidence from genetic and clinical studies for the involvement of the glutamatergic system (Harrison and Weinberger, 2005). Alternative pharmacological models of schizophrenia have been developed (Carlsson et al., 2001) based on the schizophrenia-like clinical presentations following NMDA antagonist administration. Therefore, the emerging role of glutamatergic neurotransmission in the pathophysiology of schizophrenia has gained extensive attention (Olney and Farber, 1995; Lane 2010; Tsai and Lin, 2010; Insel 2010). This has lead researchers to focus on glutamatergic neurotransmission and NMDARs as a basis for new drug development (Kantrowitz and Javitt, 2011).

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Figure 1. Glutamate/glutamine metabolism at glutamatergic synapses. Glutamate is synthesized and stored within presynaptic nerve terminals. Glutamate formation occurs by the action of glutaminase (GLNase) through a process of transamination. Newly synthesized glutamate is packaged and stored in high concentration within vesicles. After release of glutamate from the nerve terminal into the synaptic cleft, it is taken up into astrocytes by glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST) and where it is converted to glutamine by glutamine synthetase (GS). By efficient glutamate uptake systems the action of glutamate is thus terminated. Glutamine is then cycled back to the nerve terminal, where it participates in the replenishment of transmitter stores of glutamate. Some glutamatergic nerve terminals contain the excitatory amino acid carrier-1 (EAAC1), which uptakes glutamate directly. The ionotropic glutamate receptors, including N-methyl-D-aspartate (NMDA), Įamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate subtypes, are located in the postsynaptic membrane. They participate in synaptic transmission by directly opening ion channels upon glutamate binding, allowing cation influx (Na+, Ca2+) and causing excitatory post-synaptic current (EPSC) and largely function to mediate fast synaptic transmission. Among them, NMDA R is the subtype with strongest implication in the pathophysiology of schizophrenia. Glutamate and aspartate are agonists; glycine and D-serine are co-agonist of the NMDAR. D-serine is synthesized by serine racemase from L-serine. D-serine is localized to both neurons and astrocytes and is uptaken by arginine-serine-cysteine transporter-1(ASC-1). D-serine is metabolized by D-amino acid oxidase (DAAO) into hydroxyl pyruvate. Role of D-amino acid oxidase activator (DAOA, G72) as an activator or inhibitor is unclear. Glycine is uptaken by glycine transporter-I (GlyT-1) and metabolized to L-serine by glycine cleavage system (GCS). Sarcosine inhibits the glycine uptake through GlyT-1. The known potential regulators and drug targets of NMDA synapse include the “glycine” co-agonist site, serine racemase, DAAO, DAOA (G72), GlyT-1 and ASC-1. AMPA receptor possesses the quality of being mobile and they function cooperatively with NMDAR to maintain overall integrity of the glutamatergic synapses. Activation of AMPA receptor depolarizes the synaptic membrane to allow Ca2+ influx through unblocked NMDA channels in a voltage-dependent manner. The metabotropic glutamate receptors (mGluR), mGluR1-8, have a diverse synaptic localization and function pre- and postsynaptically to modulate neurotransmitter release and postsynaptic excitability, respectively. Group I receptors, consisting of mGluR1 and mGluR5, function predominantly to potentiate both presynaptic glutamate release and postsynaptic NMDA neurotransmission via secondary messengers and modulation of voltage-gated calcium currents, thus increase the activity of NMDAR. Conversely, group II (mGluRs 2 and 3) receptors serve to limit glutamate release, particularly during conditions of excitotoxity, from the synaptic cleft.

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The discovery and investigation of novel compounds targeting NMDARs will provide new insights into the mechanisms of action and range of activities of these compounds as therapeutic agents for the treatment of schizophrenia.

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2. GLUTAMATERGIC HYPOTHESIS Blockade of D2 receptor has been an obligatory mechanism of action present in the typical antipsychotics, which treat positive symptoms of schizophrenia effectively and have been approved by regulatory agencies since 1950s. In addition to D2 receptor blockade, 5HT2A receptor blockade plays a contributory role in the actions of the atypical antipsychotics (Marek et al., 2010), thus has advantages over typical antipsychotics in terms of greater efficacy for improving positive and negative symptoms, some beneficial effects on cognitive function, and fewer extra pyramidal side effects and tardive dyskinesia (He et al., 2009). Nevertheless, these medications still have limited efficacy, especially in treating the cognitive and negative symptoms of schizophrenia, and are associated with serious metabolic adverse effects (Hui et al., 2010; Marek et al., 2010). Multiple lines of evidence support the notion that the dysfunction in glutamate-glutamine cycle and glutamatergic NMDAR is involved in schizophrenia pathophysiology. Kim et al. (Kim et al., 1980) were among the first investigators to propose a glutamate hypothesis of schizophrenia, based on findings of reduced cerebrospinal fluid (CSF) levels of glutamate in schizophrenic patients compared with normal individuals. Studies of post-mortem brain and CSF have revealed a lower density of glutamatergic receptors and lower level of glutamate in schizophrenic patients than in healthy comparison subjects (Mechri et al., 2001). Studies of CSF of drug-free or drug-naive schizophrenics revealed decreased concentration of gammaglutamylglutamine which may reflect a deficiency in the gamma-glutamyltransferase system, a system probably involved in glutamate uptake, or a deficiency in glutamine (Do et al., 1995), lower indices of glutamatergic neurotransmission using CSF glutamatergic markers in correlation to more prominent thought disorder (Tsai et al., 1998), and elevated glutamine/glutamate ratio in comparison to healthy controls (Hashimoto et al., 2005). Neuroimaging studies suggested cortical hypofunction, mediated by glutamatergic neurotransmission, during rest or the performance of cognitive tasks (Marek et al., 2010). Among these findings, the most compelling evidence is provided by the psychomimetic effects of the NMDA antagonists, phencyclidine (PCP) and ketamine (Mechri et al., 2001). Over the last 2 decades, the relationship of NMDA function and schizophrenia is evidenced by the effects of the noncompetitive antagonists of NMDAR. Both PCP and ketamine induce psychiatric and physiological changes resembling schizophrenia more closely than the symptoms induced by amphetamine, a dopamine agonist (Javitt and Zukin, 1991; Krystal et al., 1994; Radant et al., 1998; Kudoh et al. 2002). As opposed to amphetamine/dopamine model, PCP induces not only positive symptoms similar to amphetamine, but also negative symptoms and cognitive deficits associated with schizophrenia (Krystal et al, 1994; Adler et al., 1999; Umbricht et al., 2000; Nabeshima et al., 2006; Mouri et al., 2007). The physiologic manifestations of schizophrenia such as hypofrontality, impaired prepulse inhibition and enhanced subcortical dopamine release are demonstrated by these antagonists as well (Coyle et al., 2002). These findings suggest that

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symptoms observed in schizophrenic patients could possibly arise from attenuated NMDARmediated neurotransmission. It was further postulated that the psychomimetic effects may not be contributed by noncompetitive antagonists alone but could be a result of any dysfunctional attenuation of the NMDAR-mediated neurotransmission (Tsai 2008). These clinical observations also have led to the idea that NMDARs that regulate mesolimbic and mesocortical dopamine pathways may be hypoactive in schizophrenia (Tamminga et al., 1995; Jentsch and Roth, 1999; Goff and Coyle, 2001; Stahl 2008). Glutamate and dopamine have been reported to exhibit reciprocal actions at subcortical structures (Nieollon et al., 1983). A descending glutamatergic pathway projecting from cortical pyramidal neurons to dopamine neurons in the ventral tegmental area (VTA) normally acts as a brake on the mesolimbic dopamine pathway through an inhibitory Ȗaminobutyric acid (GABA) interneuron in the VTA, resulting in tonic inhibition of dopamine release from the mesolimbic pathway. Hypoactive NMDARs in the VTA in untreated schizophrenia may fail to tonically inhibit mesolimbic dopaminergic neurons; this would cause mesolimbic dopamine hyperactivity and thus the positive symptoms. Unlike the actions of cortico-brainstem glutamatergic neurons on mesolimbic dopaminergic neurons where they act via an intermediary GABA interneuron, cortico-brainstem glutamatergic neurons synapse directly upon those dopaminergic neurons in the VTA that project to the cortex, those socalled mesocortical dopaminergic neurons, and normally function to tonically excite them. Therefore hypoactive NMDARs in the VTA would cause mesocortical dopamine hypoactivity, implicating the cognitive deficits (Tamminga et al., 1995; Jentsch and Roth, 1999; Goff and Coyle, 2001; Stahl 2008). Complementary to the dopamine and serotonin hypotheses, the role of NMDA hypofunction model of schizophrenia has gained extensive attention (Deutsch et al., 1989; Coyle et al., 1993; Tsai et al., 1995; Mohn et al., 1999; Farber et al., 1999; Green et al., 2000). To further support that the glutamatergic hypofunction hypothesis is not in conflict with a role for dopamine in the pathogenesis of schizophrenia or with the current therapeutic approach, which relies on drugs that act either through dopamine receptor blockade or the combined antagonism of dopamine and serotonin receptors (Meltzer 1991), a rodent study demonstrated that persistent NMDARs blockade produced a rapid and profound decrease in the levels of D2 receptor mRNA and receptor density, suggesting the important role of NMDARs in the expression of D2 receptors in basal ganglia and the interaction between glutamate and dopamine regulate the functions of the basal ganglia (Qin et al., 1994). It was further proposed that dopamine receptor blockade might act to balance glutamatergic insufficiency (Carlsson et al., 1997). Consequently, enhancement of NMDARmediated neurotransmission has been proposed as having the therapeutic potential.

3. GLUTAMATE RECEPTORS: SUBTYPE, STRUCTURE, MECHANISM AND FUNCTION Glutamate receptors are found throughout the mammalian brain. They are located in the pre- and postsynaptic membrane, where they are activated by neurotransmitters released from the presynaptic cell. Glutamate and aspartate are their natural ligands (Speranskiy and Kurnikova, 2005). Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells and one of their major functions appears to be the

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modulation of synaptic plasticity, which is vital for learning and memory, sensory transmission and coordination, and control of respiration and blood pressure (Stoll et al., 2007). Glutamate receptors are classified into two major groups, ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs), according to the signal transduction mechanism by which their activation gives rise to a postsynaptic current or lead to G-protein activation (Palmada and Centelles, 1998) (Figure 1). iGluRs comprise a family of ligand-gated ion channels (Stoll et al., 2007). An increase or decrease in surface expression of ionotropic glutamate receptors on a post-synaptic cell may lead to long-term potentiation (LTP) or long-term depression (LTD) of that cell, respectively (Asztély and Gustafsson, 1996; Pérez-Otaño 2005; Kennard et al., 2009). mGluRs may modulate synaptic plasticity by activating a signaling cascade that involves G proteins, secondary messenger systems, and subsequent post-synaptic protein synthesis (Weiler and Greenough, 1993). Three subtypes of iGluRs are identified and named NMDA, AMPA (alpha-amino-3hydroxy-5-methyl-4-isoxazole-4-propionic acid), and kainate receptors (Hollmann and Heinemann, 1994). Metabotropic glutamate receptors are all named mGluR and are divided into 3 groups based on sequence identity, second messengers, and subsequent downstream cascades they initiate: mGluRI, mGluRII, and mGluRIII (Nakanishi 1994; Chu 2000; Hinoi et al., 2001; Endoh 2004; Bonsi et al., 2005). The longest-known and best-studied glutamate receptors are iGluRs; among them NMDAR is the subtype with strongest implication in the pathophysiology of schizophrenia.

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3.1. Ionotropic All iGluRs are ligand-gated cation channels, which participate in synaptic transmission by directly opening ion channels upon glutamate binding, allowing ion flow (K+, Na+, Ca2+) and causing excitatory post-synaptic current (EPSC), which is depolarizing and if in abundance may trigger an action potential in the post-synaptic neuron (Baskys 1992). Ionotropic receptors are located in the postsynaptic membrane and play critical roles in synaptic plasticity (Stoll et al., 2007). AMPA and kainate receptors play the primary role in mediating fast excitatory postsynaptic potentials responsible for excitatory neurotransmission, whereas NMDAR, mediate the slower component of the excitatory postsynaptic potential (Goff and Coyle, 2001). At many synapses in the brain, transient activation of NMDARs leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors. Kainate receptors can also act as the induction trigger for long-term changes in synaptic transmission (Bortolotto et al., 1999). These disparate functions suggest alternate modes of regulation.NMDAR plays a critical role in a major form of use-dependent synaptic plasticity known as LTP (Lynch 2004). In LTP, a brief period of high-intensity excitatory synaptic activity, which markedly depolarizes the neurons and recruits NMDARs, results in a subsequent persistent increase in synaptic efficacy. LTP is the underlying mechanism of memory formation and learning at cellular level (Bliss and Collingridge, 1993; Cooke and Bliss, 2006).

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3.2. Metabotropic Metabotropic glutamate receptors, which belong to subfamily C of G protein-coupled receptors, are divided into three groups based upon functional activity and structure (Marino and Conn, 2006), with a total of eight subtypes. The mGluRs are composed of three distinct regions: the extracellular region, the transmembrane region, and the intracellular region (Barbado 2009). The extracellular region is composed of a Venus Flytrap (VFT) module that binds glutamate (Pin and Acher, 2002) and a cysteine-rich domain that is thought to play a role in transmitting the conformational change induced by ligand binding from in the VFT module to the transmembrane region (Muto et al., 2007). The transmembrane region consists of seven transmembrane domains and connects the extracellular region to the intracellular region where G protein coupling occurs (Pin and Acher, 2002). Glutamate binding to the extracellular region of an mGluR causes G proteins bound to the intracellular region to be phosphorylated, affecting multiple biochemical pathways and ion channels in the cell (Platt 2007). By the complex signal transduction and anatomical distribution, mGluRs can either increase or decrease the excitability of the post synaptic cell, thereby causing a wide range of physiological effects. mGluRs are linked to second messenger systems and affect neuronal metabolism, leading to alterations in glutamate release. Proteins called PDZ proteins frequently anchor mGluRs near enough to NMDARs to modulate their activity (Barbado et al., 2009). Group I receptors, consisting of mGluR1 and mGluR5, function predominantly to potentiate both presynaptic glutamate release and postsynaptic NMDA neurotransmission (Herrero et al., 1992; Rodriguez-Moreno et al., 1998; Reid et al., 1999; Thomas et al., 2000), thus increase the activity of NMDARs (Dingledine et al, 1999; Goto et al., 2009). Conversely, group II (mGluRs 2 and 3) and Group III (mGluRs 4, 6, 7 and 8) receptors serve to limit glutamate release, particularly during conditions of excitotoxity, from the synaptic cleft (Trombley and Westbrook, 1992; Pin and Duvoisin, 1995; Takahashi et al., 1996). Overall, mGluRs have been shown to be involved in neurotoxicity and neuroprotection (Siliprandi et al., 1992; Baskys et al., 2005) in addition to synaptic plasticity (Endoh 2004; Bonsi et al., 2005) (Figure 1). Excitotoxicity is a pathological process by which overstimulation of glutamate receptors causes neurodegeneration and neuronal damage. This occurs when excessive glutamate overactivate glutamate receptors (specifically NMDARs), causing high levels of calcium influx into the postsynaptic cell (Dubinsky 1993), which in turn activate a cascade of cell degradation processes recruiting proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures to result in cell death (Manev et al., 1989). Selective activation of group I mGluR has been shown to increase glutamate release from cortical neurons (Strasser et al., 1998), increase neuronal excitability (Anik-sztejn et al.,1991), upregulate NMDA-mediated currents in hippocampal and striatal cells (Fitzjohn et al., 1996), and potentiate NMDA-induced neuronal death (Strasser et al., 1998). On the other hand, agonists of group II (Platt 2007) and III mGluRs tend to protect neurons from excitotoxicity (Weaver et al., 1996; Gill et al., 1998) by reducing NMDAR activity (Conn et al. 2005). The significance of glutamate receptors in excitotoxicity was associated with many neurodegenerative diseases. Schizophrenia is one of these diseases thought to be mediated, at least in part, through stimulation of glutamate receptors (Beal 1992; Gillessen et al., 2002).

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Metabotropic glutamate receptors are also considered to affect dopaminergic and adrenergic neurotransmission (Carlsson et al., 2001; Wang and Brownell, 2007). The research in this area is at a relatively early stage. At present, agonists and antagonists for mGluRs are under preliminary clinical trials with equivocal results (Patil et al., 2007; Kinon et al., 2011).

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3.3. NMDARs The NMDAR has been demonstrated to play an important role in neurocognition and neurotoxicity (Lipson and Rosenberg, 1994; Kalia et al., 2008). It is the best studied and most relevant subtype of glutamate receptors to the understanding of the pathophysiology of schizophrenia. Blockade of the NMDAR result in psychosis resembles the clinical manifestations of schizophrenia. NMDARs are delineated from the other subtypes of glutamate receptor in a number of significant ways. First, NMDARs are gated both by ligand binding and cell membrane voltage due to a voltage-dependant block of the ion channel by the divalent cation magnesium (Nowak et al. 1984, Ascher et al. 1988). Second, binding of both agonist and co-agonist at distinct sites are required for full activation of these receptors (Johnson and Ascher, 1987; Currás and Pallotta, 1996). Third, in addition to permeability to potassium and sodium, they also have a considerable permeability to calcium (Ascher and Nowak, 1988), a property that has implications for learning and memory (Malenka and Nicoll, 1999), ischemic neuronal death as well as neurodegenerative diseases (Choi 1988; Choi and Rothman, 1990; Meldrum and Garthwaite, 1990; Lee et al. 1999). The pharmacologic regulation of the NMDAR involves the unique combination of binding sites (Hollmann and Heinemann, 1994; Wheal and Thomson, 1995). A primary agonist site is for the binding of glutamate or aspartate. A separate co-agonist site for glycine or other endogenous ligands (such as D-serine) must also be occupiedbefore glutamate can activate the ion channel. The glutamate, glycine, and magnesium binding sites are important for receptor activation and gating of the ion channel (Westbrook and Mayer, 1987). Modulatory binding sites for polyamines, protons, neuropeptides, and zinc have also been identified. In contrast, the zinc and polyamine sites are not required for receptor activation, but affect the efficacy of the channel. The polyamine site (Ranson and Stec, 1988; Williams et al., 1994) binds compounds such as spermine or spermidine, either potentiating (Ranson and Stec, 1988; Williams et al., 1994) or inhibiting (Williams et al., 1994) the activity of the receptor, depending on the combination of subunits forming each NMDAR (Williams et al., 1994). Protons inhibit these receptors (Chen and Lipton, 2006). Zinc blocks the channel in a voltage-independent manner (Westbrook and Mayer, 1987) (Figure 2). The NMDAR channel is highly permeable to Ca2+ and Na+, and its opening requires simultaneous binding of glutamate and postsynaptic membrane depolarization (Nowak et al., 1984; Monaghan et al., 1989: 8036251; McBain and Mayer, 1994). Apart from other ligandgated ion channels, NMDARs are very effectively blocked by magnesium in a voltagedependent manner (Nowak et al., 1984; Mayer et al., 1984; Jahr and Stevens, 1990) (Figure 2). At resting membrane potential, the channel of NMDAR is blocked by magnesium. Partial depolarization of the cell membrane caused by activation of the kainate and/or AMPA receptors removes magnesium, allowing the NMDA channel to open for ionic influx (Mayer et al., 1984.; Johnson and Ascher, 1990; Goff and Coyle, 2001). Calcium flux through the

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NMDAR channels exerts a number of important functional consequences (Lynch et al., 1983; Komuro and Rakic, 1993; Malenka et al., 1998). The NMDAR-mediated increase in postsynaptic Ca2+ activates kinases, including CaMKII, PKA, PKC, and mitogen-activated protein kinase (MAPK), as well as protein phosphatases, such as calcineurin. CaMKIImediates phosphorylation of the GluA1 subunit of the AMPA receptor, promotes its incorporation into the synapses, and increases AMPA receptor channel conductance, resulting in LTP. In contrast, calcineurin-triggered dephosphorylation promotes AMPA receptor internalization and thus LTD (Malenka and Bear, 2004). Activated PKC promotes synaptic incorporation of NR2A-containing NMDARs (Lau and Zukin, 2007). Concomitant scaling-up or -down AMPAR and NMDAR responses maintains the synaptic strength and neuronal excitability in an optimal range. This process, referred to as homeostatic plasticity or synaptic scaling, is critical for optimal information transfer in the nervous system (Benarroch 2011). There also exists a PCP receptor site, where non-competitive antagonists such as PCP ketamine and MK-801 bind, within the NMDA ion channel which is composed of both NR1 and NR2 subunits (Figure 2). This binding is dependent on the state of the ion channel (open or closed).

Figure 2. Schematic diagram of NMDA receptor subunits and the binding sites. The NMDA receptor forms tetrameric channels comprising two copies of NR1 and NR2 (A-D) subunits. The receptor is gated by the agonists aspartate/glutamate and the co-agonist glycine (or D-serine, D-alanine, Dcycloserine). Magnesium is a channel blocker which blocks the channel at resting membrane potential and is released upon depolarization. The NMDA receptor ionophore is highly permeable to Ca2+ and Na+, and its opening requires simultaneous binding of glutamate and postsynaptic membrane depolarization. Zn2+, zinc, blocks the channel in a voltage-independent manner. The polyamine site binds compounds, which either potentiating or inhibiting the activity of the receptor, depending on the combination of subunits forming each NMDAR. Non-competitive antagonists such as phencyclidine (PCP), ketamine, and MK-801 bind the PCP site at the channel.

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Non-competitive antagonists gain access to their receptor only via open channels (Starmer and Grant, 1985). Thus binding of PCP to the receptor site is enhanced in the presence of NMDA agonists (Reynolds et al., 1987). In other words, the binding of noncompetitive antagonists requires the interactions of multiple sites within the NMDAR. The NMDAR is composed of multiple subunits including NR1 and either NR2 (NR2 AD) or NR3 (NR3 A-B) to form heteromeric receptor-channels with different pharmacologic and biophysical characteristics (Laurie and Seeburg, 1994) (Figure 2). NR1 and NR2(A-D) subunits are obligatory for a functional NMDAR, and contain binding sites for glycine (glycine B site) and glutamate respectively. Further, receptors containing NR2A subunits have a higher affinity for compounds that bind to the glutamate agonist site, whereas receptors with NR2A or NR2B subunits havehigher affinities for MK-801 binding than do receptors withNR2C or NR2D subunits (Lynch et al., 1994). Receptors with NR2B subunits are associated with a higher affinity for polyaminemodulators (Lynch et al., 1994; Gallagher et al., 1996). Receptors containing NR2C and NR2D subunits have low conductance openings and reduced sensitivity to Mg2+ block (Yamakura and Shimoji, 1999; Cull-Candy et al., 2001; Paoletti and Neyton, 2007). The NR3 subunit is almost completely insensitive to Mg2+ block at hyperpolarized potentials (Sasaki et al., 2002), and it acts in a dominantnegative manner to suppress NMDAR activity by reducing Ca2+ permeability and surface expression of the receptors (Matsuda et al., 2003). NR2 subunits show distinct regional and developmental distribution, with NR2A and NR2B being expressed primarily in the forebrain, NR2C in cerebellar granule cells and NR2D being expressed during fetal development in the midbrain and diencephalon. NR3 subunits require both NR1 and NR2 subunits to form functional NMDARs. NR3A receptors are expressed primarily during development, and NR3B are only found in somatic neurons in brainstem and spinal cord (Mayer et al., 1989; Stone 2011). Therefore, the activity of NMDARs would depend on unique binding properties to the NMDARs, differential subunit combinations and regional distributions. In schizophrenia, the mRNA expression of the NR2A subunit of the NMDAR has been found to be decreased in a subset of inhibitory interneurons in the cerebral cortex (Bitanihirwe et al., 2009). Imaging studies using a novel SPECT tracer for the NMDAR (123I)CNS-1261 (Pilowsky et. al. 2005) have reported reduced NMDAR binding in the hippocampus of medication-free patients. This study represents the first direct demonstration of NMDAR deficiency in schizophrenia, but it remains to be replicated in a larger group of patients. The role of glutamatergic neurons in regulating other neurons’ function have been strongly implicated in the pathophysiology of schizophrenia. These include GABA interneurons (Lewis et al., 2005) and dopamine neurons, which are dependent on the activation of NMDARs (Johnson et al., 1992). The findings of clinical efficacy of D2 receptor antagonist and increased probability of developing schizophrenia after cannabis use during adolescence are consistent with deficient NMDAR function in schizophrenia and provide the key pharmacological clues to the pathophysiology of schizophrenia (Moghaddam 2005). Cannabinoid CB1 receptor and D2 receptors are localized presynaptically on glutamate terminals and work to inhibit the release of glutamate. Cannabis, reduces glutamate release, in particular in corticostriatal regions (Gerdeman and Lovinger, 2001), leading to deficient activation of NMDARs, whereas reduced D2 receptor function produces modest increases in glutamate release (Yamamoto and Davy, 1992; Cepeda et al., 2001).

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Clinically, augmentation through the NMDA-glycine site is preferred to avoid the excitotoxicity mediated through the glutamate site (Coyle 1993; Leeson 1994; Javitt 2004, 2008; Kantrowitz et al., 2010; Lane et al 2010). Other than glycine, endogenous ligands, such as D-serine and D-alanine, also bind the co-agonist site (Johnson and Ascher, 1987). Dalanine, which is present only in the pituitary, is less likely to play a physiological role in the neocortex, thus most studies focused on the binding of D-serine and glycine on the Dserine/glycine site of NMDAR (Furukawa and Gouaux, 2003). Distribution of D-serine parallels to that of NR1 subunit of NMDAR (Schell 2004) and D-serine is up to three times more potent than glycine at the glycine site of the NMDARs (Matsui et al., 1995; Schell et al., 1995; Wolosker et al., 1999b). Interestingly, serine racemase (SR), which converts L-serine to D-serine, has a parallel distribution as D-serine (Schell et al., 1997; Wolosker et al., 1999a; Yasuda et al., 2001) while D-amino acid oxidase (DAAO), which metabolizes D-serine, has a reciprocal anatomical distribution from D-serine (Figure 1).

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3.4. Non-NMDA Ionotropic Receptors AMPA Receptors AMPA receptors are dynamic components of the postsynaptic density as they possess the quality of being mobile (Lüscher and Frerking, 2001). They mediate most of the fast excitatory transmission in the mammalian central nervous system and they function cooperatively with NMDARs in the brain to maintain overall integrity of glutamatergic synapses (Bekkers and Stevens, 1989; Young and Fagg, 1990; Desce et al., 1992; Raiteri et al., 1992). Activation of AMPA receptor depolarizes the synaptic membrane to allow Ca2+ influx through unblocked NMDA channels in a voltage-dependent manner (Figure 1). Ca2+ influx, in turn, is required (Beattie et al., 2000; Lu et al., 2001) to trigger AMPA trafficking to the synaptic membrane which are critical for normal synaptic function and plasticity (Malinow and Malenka, 2002; Bredt and Nicoll, 2003). The trafficking of AMPA receptors to and away from the synaptic plasma membrane plays an essential role in both LTP and LTD, respectively (Malenka 2003). LTP and LTD in the hippocampal region of the brain are two forms of synaptic plasticity that increase or decrease the strength of synaptic transmission, respectively (Sanderson and Dell'Acqua, 2011). Therefore agents that potentiate neurotransmission via one type of glutamate receptor would permit activation of other types as well. Recently, several proteins that interact with AMPARs have been identified and they are involved in the subcellular localization, synaptic stabilization, and kinetics of AMPA receptors (Hammond et al., 2010). The findings of an alteration of forward trafficking of AMPA receptors as well as changes in the subcellular localization of an AMPA receptor subunit in schizophrenia have also been implicated in the pathophysiology of schizophrenia (Hammond et al., 2010, 2011), however future investigations are warranted to understand the underlying mechanism. AMPA receptors desensitize quickly following direct stimulation. Thus, direct agonists have limited prolonged stimulatory effect. However, indirect modulators, termed ampakines, may be able to stimulate AMPA receptors without causing desensitization. Ampakines have been found to stimulate cognitive performance in animal models (Hampson et al., 1998), and are currently under development for treatment of cognitive disorders such as schizophrenia,

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Alzheimer’s disease, or aging-related memory decline. But there is no convincing finding thus far.

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Kainate Receptors Kainate receptors are composed of the low affinity GluR5-7 subunits and the high affinity KA1 and KA2 subunits (Hollmann and Heinemann, 1994). The GluR5-7 subunits assemble into homomeric complexes, or heteromerically coassemble with KA1 and KA2, resulting in receptors with distinct pharmacological properties, suggesting that subunit composition, at least in part, determines the functional properties of the kainate receptor (Lerma 1998). The functions of kainate receptors have begun to be elucidated for their role in synaptic transmission and plasticity in the brain in the last decade. Some of the actions of kainate receptors are ionotropic, others seem to utilize noncanonical signaling pathway by linking receptor activation to G-proteins and second-messenger cascades and invoke metabotropic roles. Specific subunits of kainate receptors have been demonstrated to associate with G proteins. Therefore, kainate receptors expedite long-lasting signaling by novel metabotropic modes of action (Lerma 2003; Rodríguez-Moreno and Sihra, 2007). Kainate receptor binding has been studied in multiple brain regions in schizophrenia by several independent groups. [3H]kainate binding has been reported to be elevated in multiple cortical areas in schizophrenia (Nishikawa et al. 1983; Deakin et al. 1989), decreased in the hippocampus, parahippocampal gyrus (Kerwin et al., 1990) and infragranular laminae of the prefrontal cortex (Meador-Woodruff et al., 2001), and unchanged in striatal regions (Nishikawa et al., 1983; Noga et al., 1997). These data add to the growing literature implicating ionotropic glutamate receptor disturbances in schizophrenia, and indicate that in addition to AMPA and NMDARs, the kainite receptors are also abnormally expressed in this illness.

4. EVIDENCE OF NMDAR HYPOFUNCTION IN SCHIZOPHRENIA 4.1. Clinical Studies Hypofunction of NMDAR mediated neurotransmission as a critical deficit in schizophrenia (Olney and Farber, 1995; Bachus and Kleinman, 1996; Coyle, 1996) is further evidenced by the effects of the noncompetitive antagonists of NMDAR, PCP and ketamine, both of which possess the function of binding to a site within the ion channel of the NMDAR that blocks cation influx. Unlike catecholamine agonists, they can produce psychiatric and physiological changes closely associated with schizophrenia (Krystal et al., 1994; Radant et al., 1998; Kudoh et al., 2000). Chronic PCP abusers have commonly been misdiagnosed as being schizophrenic (Luby et al., 1959; Allen and Young, 1978), thus PCP mirrors the symptomatology of schizophrenia almost completely. These findings attracted the attention of neuroscientists and a series of clinical studies in order to understand the mechanisms underlying this debilitating disease and advance the therapeutic strategies based upon the NMDA perspective were conducted

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4.1.1. Nonpsychotic Subjects Studies of PCP in nonpsychotic population showed that these individuals with administration of subanesthetic doses of PCP demonstrated neuropsychological and behavioral psychopathology similar to that observed in schizophrenia (Rosenbaum et al., 1959; Luby et al., 1959; Davies and Beech, 1960; Cohen et al., 1962) while acutely PCPintoxicated individuals were virtually indistinguishable from symptomatic schizophrenic patients (Allen and Young, 1978). Placebo-controlled, double-blind studies of the effects of NMDA antagonists in humans have been limited as highly potent PCP induced pathomorphological changes in rat brain (Olney et al., 1989) and has been associated with prolonged psychotic episodes in humans (Allen and Young, 1978). The safety of these agents in the clinical management of neurodegenerative diseases were the major concerns. Ketamine, with lower binding affinity to NMDAR and potency than PCP (Anis et al., 1983), produces minimal cardiac and respiratory effects and its anesthetic and behavioral effects remit soon after administration (Pandit et al., 1980; Moretti et al., 1984). When subanesthetic dose (0.3-0.5 mg/kg) was infused intravenously to nonpsychotic subjects, ketamine produces an amotivational state characterized by blunted affect, withdrawal, and psychomotor retardation (Cohen et al., 1962) as well as psychotic symptoms in the form of suspiciousness, disorganization, and visual or auditory illusions (van Berckel 1998). Significant increase in Brief Psychiatric Rating Scale (BPRS) total scores and other composite scores (SANS and SAPS) were observed (van Berckel 1998; Hetem et al., 2000). Dissociative symptoms are also prominent, with depersonalization in particular as an important early feature of the schizophrenia prodrome (Krystal et al., 1994). During smooth pursuit eye tracking, ketamine induces nystagmus and oculomotor abnormalities that resemble some of the deficits seen in schizophrenia (Friedman et al., 1991; Radant et al., 1998; Mechri et al., 2001). Cognitive deficits were demonstrated by impaired performance on the Wisconsin Card Sorting Test, continuous performance vigilance test, verbal declarative memory, delayed word recall, and verbal fluency tests (Cohen et al., 1962; Krystal et al., 1994; Malhotra et al., 1996; Newcomer et al., 1999). 4.1.2. Schizophrenic Patients Studies in stable schizophrenic patients provided more clues to the possible underlying etiology of schizophrenia. Studies with administration of subanesthetic doses of PCP (0.1 mg/kg) to chronic schizophrenics, dramatic exacerbation of schizophrenic symptoms was observed (Luby et al., 1959; Lasagna and Pearson, 1965). Patients became more assertive, hostile, and unmanageable, and these changes lasted not a few hours (as in nonpsychotic population) but from four to six weeks (Luby 1981), suggesting the vulnerability of this population to further insult of NMDA function. Similarly, studies with subanesthetic dose of ketamine, showed an exacerbation or worsening of positive and negative symptoms with further decrements in recall and recognition memory in stable schizophrenic patients (Lahti et al., 1995; Malhotra et al., 1997; Tamminga 1999; Mechri et al., 2001). 4.1.3. Animal Models Other evidences are provided by the animal models. One study with rats repeatedly treated with PCP and MK-801(another NMDA channel blocker) under an escalating dosing regimen produced a stable and persistent disruption of prepulse inhibition (PPI). Startle

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magnitude increased progressively and dose-dependently (Li et al., 2011). Two other studies with rats treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes persist even after withdrawal from repeated PCP treatment (Nabeshima et al., 2006; Mouri et al., 2007). One study with rats under sub-chronic PCP treatment demonstrated impaired 5-Choice Continuous Performance Test (CPT) performance in a way consistent with impaired vigilance in patients with schizophrenia (Barnes et al., 2011). A recent study with rats under subanesthetic dose of ketamine treatment showed hyperlocomotion and stereotypic movements and changes in the activity of respiratory chain complexes in multiple brain regions at different time points (de Oliveira et al., 2011). Several studies further investigate the acute effects of the non-competitive NMDA antagonists on the gene expression of several enzymes, which were suggested to play important roles in the regulation of NMDAR via D-serine metabolism. Ketamine administration in rats produced a dose-dependent and transient elevation in the levels of serine racemase (SR) and D-amino acid oxidase (DAAO) mRNAs in all the brain areas (Takeyama et al., 2006). SR is an enzyme present in glial cells, where it isomerizes L-serine into D-serine. DAAO catalyzes oxidative deamination of D-amino acids (stereoisomers of naturally occurring L-amino acids) (Krebs 1935), thus degrades D-serine. MK-801 administration in rats also produced a significant increase in the expression of SR mRNA in almost all brain areas (Yoshikawa et al., 2004; Hashimoto et al., 2007), whereas no significant changes were found in the level of DAAO mRNA in most brain areas (Yoshikawa et al., 2004). In addition, the administration of MK-801 caused a slight but significant elevation in the concentrations of D-serine in the cortex and striatum (Hashimoto et al., 2007). These findings suggest that there is a relationship between the blockade of the NMDARs and the gene expression of the D-serine-related metabolic enzymes.

5. NMDA-ENHANCING AGENTS Novel therapeutic agents are under development aiming to treat the core symptoms of schizophrenia, particularly the negative symptoms and cognitive deficits, by enhancing NMDA function based on the hypothesis of NMDA hypofunction in schizophrenia.

5.1. NMDAR Glycine-Site Agonists The NMDAR is unique in that in addition to the glutamate recognition site, it also contains a coagonist site that binds the endogenous full agonists, glycine and D-serine (Dunlop and Neidle, 1997; Snyder and Kim, 2000; Baranano et al., 2001; Tsai et al., 2006). Direct agonists of the glutamate-binding site of the NMDAR may not be clinically feasible due to the risk of neurotoxicity; therefore the allosteric sites on the NMDAR complex, particularly the coagonist site, are promising targets for drug development (Leeson and

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Iversen, 1994; Snyder and Ferris, 2000; Hui and Tsai, 2009). Thus, several approaches have emerged aimed towards modulating the glycine binding site (Kinney and Sur, 2005). D-serine is a more potent agonist than glycine at the glycine coagonist site and has a greater ability to penetrate the blood brain barrier (Hashimoto and Oka, 1997). It has been found that central and peripheral D-serine levels are reduced in schizophrenic patients, thus impaired D-serine function could contribute to NMDA hypofunction in schizophrenic patients (Hashimoto et al., 2003, 2005; Yamada et al., 2005). This implicates that D-serine administration may be beneficial in schizophrenic patients (Kinney and Sur, 2005). Several controlled clinical trials have shown that co-administration of D-serine or glycine in conjunction with antipsychotics can ameliorate some symptoms of the disorder (Tsai et al., 1998; Goff and Coyle, 2001; Heresco-Levy et al., 2005, Lane et al., 2005, 2010). D-alanine is another full agonist that binds weakly to this site but one study showed its effect on the symptoms of schizophrenic patients (Tsai et al., 2006). D-cycloserine, an anti-tuberculosis drug, is a partial agonist at the glycine coagonist site (Sawa and Snyder, 2003), thus it is the least efficacious, likely due to it being a partial agonist that acts as an antagonist at high doses (Gray and Roth, 2007). A potential limitation of targeting the glycine coagonist site is that both glycine and Dserine must be given at gram-level doses to significantly elevate central nervous system levels. Thus, other indirect approaches to activate NMDARs are being explored, such as blocking reuptake of glycine or inhibiting the metabolism of D-serine (Hui and Tsai, 2009).

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5.2. Glycine Transport Inhibitors An indirect approach is explored to augment NMDA activity via the glycine coagonist site to increase synaptic glycine by inhibiting the glycine transporter. Extracellular glycine levels can be regulated via uptake by 2 types of high affinity glycine transporters, GlyT-1 and GlyT-2 (Depoortère et al., 2005). GlyT-2 has a more limited distribution and is thought to provide the principal glycine uptake mechanism at inhibitory glycinergic synapses mainly in the brain stem and spinal cord (Liu et al., 1993; Jursky and Nelson, 1995; Zafra et al., 1995), whereas GlyT1 is widely expressed both in peripheral tissues and in the CNS where it is present predominantly on glial cells and has been proposed to mainly function at excitatory synapses by regulating glycine levels at the coagonist binding site of NMDAR (Smith et al., 1992; Berger et al., 1998; Roux and Supplisson, 2000), thus GlyT-1 plays a crucial role in maintaining the concentration of glycine within NMDA synapses at a subsaturating level. Blockade of GlyT-1 is predicted to increase extracellular glycine and thus enhance NMDAR neurotransmission. This mechanism is analogous to that of using a serotonin reuptake inhibitor to enhance serotonergic neurotransmission (Tsai 2008). The studies of GlyT-1 inhibitor, a sarcosine (N-methylglycine) analogue, N[3-(4’-fluorophenyl)3-(4’ phenylphenoxy)propyl]sarcosine (Aubrey and Vandenberg, 2001; Chen et al., 2003), and the GlyT-1 knockdown mutation have demonstrated the critical role that GlyT-1 plays in enhancing NMDA neurotransmission (Tsai et al., 2004). Sarcosine, which is an endogenous inhibitor of GlyT-1, has shown clinical efficacy while being administered as add-on therapy to typical and atypical antipsychotics or as monotherapy, thereby supporting its NMDAenhancing and antipsychotic function (Tsai et al., 2004; Lane et al., 2005, 2008, 2010).

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5.3. DAAO Inhibitors

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DAAO is a peroxisomal enzyme with FAD as cofactor (Pollegioni et al., 2007) that catalyzes oxidative deamination of D-amino acids (Khoronenkova and Tishkov, 2008) particularly the endogenous NMDAR co-agonist, D-serine. DAAO regulation of D-amino acid levels has been associated with several physiological processes ranging from hormone secretion to synaptic transmission and cognition (Smith et al., 2010). Studies of D-serine revealed lower serum levels in schizophrenia patients as compared to healthy controls (Hashimoto et al., 2003). Thus, DAAO has the potential to modulate NMDAR function and contributes to the reduction in NMDAR-mediated neurotransmission (Mothet et al., 2000) via D-serine degradation (Verrall et al., 2010). Consistently, DAAO-mediated D-serine decrements is associated with susceptibility to schizophrenia (Chumakov et al., 2002; Schumacher et al., 2004; Liu et al., 2004, 2006; Yamada et al., 2005; Wood et al., 2007). There is further evidence in support of the above notion: in postmortem studies, the gene expression (Habl et al., 2009) and mean DAAO activity are higher in the schizophrenia patients group compared with the control group (Madeira et al., 2008; Habl et al., 2009); in animal models, genetic inactivation of DAAO in rodents shows reversal of schizophrenia-like phenotypes and elevation in brain levels of D-serine (Konno et al., 2010; Labrie et al., 2008, 2010), and administering potent and selective inhibitors of DAAO to rodents affected cortical activity and produced a significant increase in NMDAR-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in hippocampal activity (Strick et al., 2011). Taken together, inhibition of DAAO may be suggestive of potential therapeutic benefits by upregulating D-serine levels.

6. SUMMARY The involvement of glutamatergic system in the pathophysiology of schizophrenia has become a new trend in the understanding of complex symptom profile of schizophrenia. A review of data in the physiology of glutamate, glutamate receptors, and their relationship to schizophrenia as evidenced by genetic and clinical studies, supports the hypothesis that NMDAR hypofunction plays a significant role in the pathophysiology of schizophrenia. Several new therapeutic agents acting as direct or indirect enhancers of the glycine coagonist site of NMDAR are yielding encouraging preliminary results. Further investigations in the molecular mechanism of the regulation of NMDAR and identification of new therapeutic targets would bring forth a revolutionary strategy to substantially improve the negative symptoms and cognition, and thereafter, quality of life in the population suffering from this disease.

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In: Glutamate: Functions, Regulation and Disorders Editors: Golda Chayat and Avital Yedidya

ISBN 978-1-61942-545-3 © 2012 Nova Science Publishers, Inc.

Chapter 3

EXTRACELLULAR OSMOLARITY MODULATES GLUTAMATE UPTAKE AND RELEASE IN NEURONS, ASTROCYTES AND SYNAPTOSOMES Tatyana V. Waseem and Sergei V. Fedorovich* Laboratory of Biophysics and Engineering of Cell, Institute of Biophysics and Cell Engineering, Akademicheskaya St., 27, Minsk 220072, Belarus

ABSTRACT

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Many pathological statements are accompanied by changing of blood sodium concentration with following fluctuation in extracellular osmolarity. That can happen surprisingly often. It is reported that hyponatremia is found in 1-2% all hospitalized patients. Changing of extracellular osmolarity leads to developing of hyperexcitability, seizures and coma with following damages of neurons. Molecular basis for this phenomenon is not clear. Glutamate is main exciting neurotransmitter. It is shown that hypotonic swelling leads to a decrease of glutamate uptake in astrocytes and synaptosomes. This treatment also induces glutamate release from vesicular and cytosolic pool in neurons, astrocytes and synaptosomes. Except exocytosis, carrier reversal, specialised channels for instance maxi-anion channels and volume-sensitive outwardly rectifying anion channels (VSOR) are involved in glutamate efflux in hypotonic conditions. Hypertonic shrinking induces calcium-independent exocytosis in both neurons and synaptosomes. We suggest that these events can be basis for hyperexcitability in hypo- and hypernatremia. Pharmacological inhibiting of glutamate efflux pathway potentially can be used for treatment of neurological symptoms in case of blood osmolarity fluctuations.

*

Corresponding author: Dr. Sergei V. Fedorovich, Institute of Biophysics and Cell Engineering, Akademicheskaya St., 27, Minsk 220072, Belarus, Tel: + 375-172-84-2252; Fax: + 375-172-84-2359, Email: [email protected]

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1. INTRODUCTION The main motivation for the ongoing World Wide research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning (McEntee and Crook, 1993).

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How does Glutamate Work as a Transmitter? Like other signaling substances (neurotransmitters and hormones) the signaling effect of glutamate is not dependent on the chemical nature of glutamate, but on how cells are programmed to respond when exposed to glutamate. At chemical synapses, glutamate is stored in vesicles. Action potential triggers release of glutamate from the presynaptic cell. Only cells with glutamate receptor proteins on their surfaces are sensitive to glutamate. Glutamate exerts its signaling function by binding to and thereby activating these receptor proteins. Several subtypes of glutamate receptors have been identified: NMDA, AMPA/kainate and metabotropic receptors (mGluR). Although the individual receptor subtypes show specific (restricted) localizations, glutamate receptors of one type or another are found virtually everywhere. Most of the nerve cells, and even glial cells, have glutamate receptors (Shigeri et al., 2004). Glutamate works not only as a point-to-point transmitter but also through spill-over synaptic crosstalk between synapses in which summation of glutamate released from a neighboring synapse creates extrasynaptic signaling/volume transmission (Uchida et al., 2010; Diamond, 2001; Rodríguez Díaz et al., 2005; Okubo and Iino, 2011). The mechanisms which can maintain low extracellular concentrations of glutamate are essential for brain function. The only mechanism for removal of glutamate from the extracellular fluid is cellular uptake of glutamate. This uptake is mediated by a family of special transporter proteins. These proteins bind glutamate, one molecule at the time, and transfer them into the cells. In agreement with the abundance of glutamate and the ubiquity of glutamate receptors, brain tissue displays a very high glutamate uptake activity (Danbolt, 2001). Glutamate is taken up into both glial cells and nerve terminals (Krantz et al., 1999). The former is believed to be the more important from a quantitative point of view. Glutamate taken up by astroglial cells is converted to glutamine. Glutamine is inactive in the sense that it cannot activate glutamate receptors, and is released from the glial cells into to extracellular fluid. Nerve terminals take up glutamine and convert glutamine back to glutamate. This process is referred to as the glutamate-glutamine cycle, and is important because it allows glutamate to be inactivated by glial cells and transported back to neurons in an inactive (nontoxic) form (Laake et al., 1995; Kvamme, 1998). Neurotransmitters are transported across the membrane by several families of transporters that diverge in their requirements of inorganic ions:

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1. Vesicular transporters – operating on both synaptic vesicles and secretory granules membranes (Schuldiner, 1994). 2. Na+/Cl- and Na+/K+-dependent transporters  operating at the plasma membrane of neurons and glial cells (Kanner, 1983; Schloss, 1992; Uhl, 1992; Amara, 1993). 3. General transport system for amino acids  maintaining the normal concentration of neurotransmitters in the extracellular space (Danbolt, 2001).

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Transport of Glutamate across the Plasma Membrane 1. High-affinity transport of glutamate. Today five subtypes of transport systems are cloned. This type of transporters is known as "excitatory amino acid transporters" (EAAT). To operate these proteins use the driving force formed by transmembrane gradient of sodium and potassium. Members of this transporters family are located mainly on the membrane of glial cells and remove glutamate from the extracellular space and from the synaptic cleft. The stoichiometry of the transporting system is not well known: nNa+:mH+:1 glutamate ion inside and 1K+ out. However, this system could subject to reversion of the transport direction and is responsible for the output of glutamate from the cells during cerebral ischemia. 2. Low-affinity transport of glutamate. These types of transport system are Na+independent. It is believed that low-affinity transport of glutamate supplies brain cells by amino acids used for metabolic pathways. 3. Na+-independent Cl--dependent transport and exchange of glutamate-cysteine. Sodium-independent chloride-dependent glutamate transport has been described in brain tissue and brain cell cultures. Normally, the transmembrane gradient of glutamate is used as a driving force for the accumulation of cysteine. However, researchers do not rule out the possibility of transporter reversion mode at high concentrations of extracellular glutamate (for review see Danbolt, 2001).

Pathology Glutamate is toxic, not in spite of its importance, but because of it. Glutamate does not only mediate a lot of information, but also information which regulates brain development and information which determines cellular survival, differentiation and elimination as well as formation and elimination of nerve contacts (synapses). From this it follows that glutamate has to be present in the right concentrations in the right places for the right time. Both too much and too little glutamate is harmful. This implies that glutamate is both essential and highly toxic at the same time. Excitotoxicity due to glutamate occurs as part of the ischemic cascade and is associated with stroke and diseases like amyotrophic lateral sclerosis, autism, some forms of mental retardation, and Alzheimer's disease (Taoufik and Probert, 2008; Milanese et al., 2011; Hu et al., 2011; Gardoni and Di Luca, 2006; Ali and Levine, 2006; Sapolsky, 2005; Hynd et al., 2004).

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Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons produces spontaneous depolarization around one second apart, and this firing pattern is similar to what is known as paroxysmal depolarizing shift in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening of voltage-activated calcium channels, leading to glutamic acid release and further depolarization. Glutamate transporters are found in neuronal and glial membranes. They rapidly remove glutamate from the extracellular space. In brain injury or disease, they can work in reverse mode, and excess glutamate can be accumulated outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death (Wang and Qin, 2010; Vincent and Mulle, 2009; Fujikawa, 2005).

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Glutamate release Mechanisms. Vesicular and Non-Vesicular The release of glutamate is triggered by the arrival of a nerve impulse (or action potential) and occurs through an unusually rapid process of vesicular secretion, also known as exocytosis: Within the presynaptic nerve terminal, vesicles containing neurotransmitter glutamate sit "docked" and ready at the synaptic membrane. The arriving action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels at the down stroke of the action potential (tail current). Calcium ions then bind with the proteins found within the membranes of the synaptic vesicles, allowing the vesicles to "dock" with the presynaptic membrane resulting in the creation of a fusion pore. The vesicles then release their contents to the synaptic cleft through this fusion pore within 180 μsec of calcium entry. Vesicle fusion is driven by the action of a set of proteins in the presynaptic terminal known as SNAREs. As a whole, the protein complex or structure that mediates the docking and fusion of presynaptic vesicles is called the active zone. The membrane added by this fusion is later retrieved by endocytosis and recycled for the formation of fresh neurotransmitter-filled vesicles (for review see Sudhof, 2000). Beginning from 70th of the former century, there was an active discussion concerning an origin of glutamate released from nerve terminals in response to depolarization (Martin, 1976, Haycock et al., 1978; DeBelleroche and Bradford, 1977). Some groups have favored a cytosolic origin for the glutamate released during neurotransmission (DeBelleroche and Bradford, 1977). At the same time, there was considerable evidence that some measure of compartmentalization exists within the terminal pointing to the vesicular release of glutamate. In 1986, Nichols and Sihara (Nicholls and Sihara, 1986) showed that about 8.5 % of glutamate stored in synaptosomes has released by calcium-dependent manner and than have provided data that a part of the newly accumulated glutamate, which may reflect a cytoplasmic pool, was released from nerve terminals by calcium-independent pathway (Nicholls et al., 1987). Similar data were received for depolarization-induced efflux of GABA (Sihara et al., 1984). In the laboratory, Adam-Vizi, in 1991 it was found that K+ and membrane depolarization forced release of glutamate, GABA and glycine even in the absence of extracellular calcium. It was assumed that a reversion of these amino acids transporters is the primary reason of such an efflux (Adam-Vizi et al., 1991) Thus, there was proved that release of glutamate and GABA occurs primarily by two main pathways: through Ca2+-dependent vesicular exocytosis and Ca2+-independent reversion of neurotransmitter transporters pumping cytosolic mediators out. Depending on the

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conditions a neurotransmitter can recycle between these both pools (Nicholls and Attwell, 1990; Sanchez-Prieto et al., 1987). Further it was proved that similar mechanisms are used for acetylcholine (Adam-Vizi, 1984), glutamate (McMahon and Nicholls, 1990) and GABA (Haycock et al., 1978). Moreover, Na+-dependent Ca2+-independent release of another neurotransmitter – GABA  was demonstrated for horizontal cells of retina, which lack synaptic vesicles, but are able to accumulate and release GABA (Adam-Vizi, 1990). Parpura in 1994 has showed that stimulation of astrocytes followed by a rise of intracellular calcium concentration caused non-vesicular furosemide-sensitive release of glutamate (Parpura et al., 1994). Except normal carriers for glutamate, such as synaptic vesicles and transporters, an emergency pathway can take part in transporting of the transmitter across membrane of neuronal cells. This pathway is represented by specific anion channels activating at some volume-coupled stimuli.

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2. THE LINK BETWEEN VOLUME REGULATION AND GLUTAMATE TRANSPORT Maintenance of cell volume is an ancient homeostatic mechanism necessary for the survival and proper function of the vast majority of cells. Alterations in cell volume can lead to a number of changes in cell function including excitability, cell-cycle progression, proliferation, apoptosis and metabolic regulation (Okada et al. 2009). However, regulation of cell volume is of particular significance to the central nervous system (CNS) because of the physical restrictions of the skull. Even small changes in brain cell volume can profoundly influence the spatial relationships between neurons, astrocytes and the extracellular space. A reduction in the latter, as occurs during brain cell swelling, will result in both an increased lateral diffusion and higher extracellular concentrations of neurotransmitters (Sykova, 2004; Thorne and Nicholson, 2006). Larger increases in brain cell volume can compress blood vessels leading to episodes of anoxia and ischaemia, and ultimately to a displacement of the brain parenchyma through the foramen magnum, leading to cardiac and respiratory arrest (Pasantes-Morales et al. 2002). Brain cells can swell either as a result of changes in intracellular ion and water distribution (isotonic swelling, as occurs in stroke or traumatic head injury) or by a reduction in plasma osmolarity (hypoosmotic swelling). The most common cause of hypoosmotic swelling is hyponatremia, which is defined as reduction in serum Na+ concentration from a normal value of 145 mequivLí1 to 136 or below (Fisher et al., 2010). Hyponatremia is the most frequently encountered electrolyte disorder in clinical practice and can arise from a wide diverse array of etiologies including congestive heart failure, syndrome of inappropriate secretion of vasopressin, liver cirrhosis, psychotic polydipsia or over-hydration, as may occur in athletes and military personnel (Bhardwaj, 2006; Lien and Shapiro, 2007). Epidemiologic studies have found that hyponatremia occurs in approximately 1–2% of hospitalized patients (Anderson et al., 1985). Its prevalence in the United States is estimated to be between 3.2 and 6.1 million patients/year (Boscoe et al., 2006). Although patients with mild hyponatremia are often asymptomatic, reductions in plasma osmolarity of >10% can elicit symptoms of nausea

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and headache whereas seizures, coma, permanent brain damage and death can occur when plasma osmolarity is chronically reduced by >20%. Hypernatremia is basically a mirror image of hyponatremia (Rose, 1994; McManus et al., 1995; Strange, 1992). The rise in the plasma sodium concentration and osmolarity causes acute water movement out of the brain; this decrease in brain volume can cause rupture of the cerebral veins, leading to focal intracerebral and subarachnoid hemorrhages and possible irreversible neurologic damage (Rose, 1994; McManus et al., 1995). The clinical manifestations of this disorder begin with lethargy, weakness, and irritability, and can progress to twitching, seizures, and coma. Severe symptoms usually require an acute elevation in the plasma sodium concentration to above 158 mequivLí1. Values above 180 mequivLí1 are associated with a high mortality rate, particularly in adults (Moder et al., 1990).

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3. OSMOLYTES AND CEREBRAL ADAPTATION TO HYPONATREMIA The degree of cerebral edema and therefore the likelihood of neurologic symptoms is much less with chronic hyponatremia (Rose, 1994; Laureno and Karp, 1997; Sterns et al., 1989). This protective response, which begins on the first day and is complete within several days, occurs in two major steps. The initial cerebral edema elevates the interstitial hydraulic pressure, creating a gradient for extracellular fluid movement out of the brain into the cerebrospinal fluid (Melton et al., 1987). The brain cells lose solutes, leading to the osmotic movement of water out of the cells and less brain swelling (Strange, 1992; Laureno et al., 1997; Melton et al., 1987; Lien et al., 1991; Verbalis and Gullans, 1991; Videen et al., 1995). Most of this volume regulatory response initially consists of the loss of potassium and sodium salts; this is then followed over the next few days by the loss of organic solutes. Electrolyte movement occurs quickly because it is mediated by the activation of quiescent cation channels in the cell membrane; organic solute loss occurs later because it requires the synthesis of new transporters (McManus et al., 1995; Strange, 1992). These processes are reversed with correction of the hyponatremia (McManus et al., 1995; Strange, 1992; Videen et al., 1995). Studies in hyponatremic animals have shown that the major osmolytes lost from the brain cells are the amino acids glutamine, glutamate, and taurine, and to a lesser degree the carbohydrate myoinositol (Strange, 1992, Lien et al., 1991; Verbalis and Gullans, 1991). A study using proton NMR spectroscopy found a slightly different pattern in humans with chronic hyponatremia; myoinositol and choline compounds were the primary organic solutes lost, with a smaller change occurring in glutamine and glutamate (Videen et al., 1995). Previous studies have indicated that during episodes of hypoosmotic stress organic osmolyte homeostasis is regulated not only via osmolyte efflux but also at the level of osmolyte reuptake (Olson and Martinho, 2006; Foster et al., 2009).

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Adaptation to Hypernatremia Beginning on the first day, however, brain volume is largely restored due both to water movement from the cerebrospinal fluid into the brain (thereby increasing the interstitial volume) (Strange, 1992; Pullen et al., 1987) and to the uptake of solutes by the cells (thereby pulling water into the cells and restoring the cell volume) (Strange, 1992; Heilig et al., 1989; Lien et al., 1990). The latter response involves an initial uptake of sodium and potassium salts, followed by the later accumulation of osmolytes, which in animals consists primarily of myoinositol and the amino acids glutamine and glutamate (Heilig et al., 1989; Lien et al., 1990). Myoinositol is taken up from the extracellular fluid via an increase in the number of sodium-myoinositol cotransporters in the cell membrane (Paredes et al., 1992), whereas the source (uptake from the extracellular fluid or production within the cells) of glutamine and glutamate is at present unknown. The net effect is that these osmolytes, which do not interfere with protein function (Videen et al., 1995), account for about 35 percent of the new cell solute (Lien et al., 1990).

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4. MECHANISMS OF OSMOLITE TRANSPORT AT OSMOTIC SHOCK – NEURONS AND ASTROCYTES Although organic osmolytes potentially contribute less than their inorganic counterparts to cell volume adaptation (35 and 65%, respectively), organic osmolytes are highly enriched in the CNS and their utilization minimizes changes in membrane potential associated with the efflux of inorganic osmolytes such as K+ or Clí. However, it should be remembered that several of the quantitatively major organic osmolytes, such as glutamate, GABA and glycine are ‘neuroactive’ and can activate their respective receptors on nearby neurons and glia. Thus, their release under conditions of volume correction is not without neurobiological consequences. Increases in Cl-current, osmolyte release, and/or RVD in response to hypoosmolarity have also been monitored in neuronal preparations such as Purkinje cells (Nagelhus et al., 1993), sympathetic ganglia (Leaney et al., 1997), cerebellar granule cells (Moran et al., 1997; Morales-Mulia et al., 2001), mouse sensory trigeminal neurons (Viana et al., 2001), human NT2-N neurons (Novak et al., 2000), neuroblastoma (Altamirano et al., 1998; Loveday et al., 2003), and primary cultures of hippocampal and cortical neurons (Li and Olson 2004; Inoue et al., 2005). Hypoosmolarity has also been demonstrated to elicit a release of organic osmolytes from brain slices (Bothwell et al., 2001) and from isolated nerve ending preparations (Tuz et al., 2004; Tuz and Pasantes-Morales 2005). Cellular mechanisms that underlie the mobilization and cellular redistribution of neuroactive osmolytes, such as glutamate, GABA or glycine during in vivo hypoosmotic hyponatremia are still disputable. While most of the evidence so far suggests an exocytosis-dependent mechanism for transmitter release in response to changes in cell volume, other mechanisms including channel- and transporter-mediated transmitter extrusion have been reported.

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4.1 Exocytosis It was well documented that hypertonic shrinking, inhibition of casein kinase II and ruthenium red are able to induce vesicular release of neurotransmitter without involving calcium (Rosenmund and Stevens, 1996; Trudeau et al., 1996; Ashton et al., 2001; Rizzoli and Betz, 2002). Further it was suggested that, similarly with hypertonicity-induced release, the hypoosmotic conditions also cause vesicular neurotransmitter release (Franco et al., 2001; Pasantes-Morales et al., 2002). This suggestion was supported by data received on synaptosomes, nerve terminals specialized for exocytosis and equipped with all vesicle release protein machinery (Wasim et al., 2003; 2005; Tuz et al., 2004). The divergence exists regarding dependency of hypoosmolarity induced exocytosis on presence of calcium. Experimental data of Waseem and co-workers are pointing to rather regulatory role of Ca2+ than triggering that which has been showed in paper of Tuz and co-workers for glutamate, GABA and norepinephrine, (Tuz et al., 2004, 2005). Potentially, at osmotic stress Ca2+independent exocytosis of neurotransmitter amino acids such as GABA and glutamate occurs in a ‘‘kiss and run’’ mode (partial fusion), while Ca2+-dependent exocytosis is mediated by full vesicle fusion (Fedorovich et al., 2005; Waseem et al., 2005). For instance, early cellular swelling during ischemia has been reported to be mediated by EAA release through Ca2+-dependent exocytosis (Katayama et al., 1992). Thus, Ca2+-dependent and –independent mechanisms both seem to mediate vesicle fusion or exocytosis during cell swelling. Activation of exocytosis by osmotic cell swelling is not unprecedented. An increase in membrane capacitance has been reported after hypoosmotic stimulation of Intestine 407 cells (Okada et al., 1992). In addition, morphometric analysis of electron micrograph images of rat hepatocytes revealed a marked enlargement of the membrane surface area within 5 min of hypotonic exposure (Pfaller et al., 1993). Furthermore, Bruck et al., (Bruck et al., 1992) observed an increase in the release of horseradish peroxidase after hypotonic stimulation from a horseradish peroxidase-loaded perfused liver. Because the horseradish peroxidase release was found to be sensitive to colchicine, the involvement of exocytosis was suggested (Bruck et al., 1992). In line with this concept, reducing the osmolarity of the surrounding medium promoted the release of fluorescein isothiocyanate-coupled dextran (72,000 Da) from preloaded inner medullary collecting duct kidney cells (Czekay et al., 1994). The mechanisms mediating the release of chemical transmitters from astrocytes are the subject of intense research (Seifert and Steinhäuser, 2011). It was suggested that astrocytes posses the necessary machinery to conduct exocytosis (Jeftinija et al., 1997; Evanko et al., 2004; Parpura et al., 2004; Malarkey and Parpura, 2008). Recent experiments have shown that hypotonic conditions stimulate the release of glutamate and ATP from astrocytes, but a mechanistic understanding of this process is not available. To determine whether hypotonicity activates the process of regulated exocytosis, the membrane capacitance has been monitored by the whole-cell patch-clamp technique whilst a hypotonic medium was applied to cultured astrocytes. It was demonstrated that capacitance measurements have the sensitivity to detect increases in cell surface area as small as 0.5%, and it has been concluded that cell swelling occurs via an exocytosis-independent mechanism, probably involving the unfolding of the plasma membrane (Pangrsic et al., 2006).

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In the rat brain in vivo it was demonstrated that hypoosmotic medium-induced release of the excitatory amino acids was not inhibited by Cd2+, which inhibits exocytosis (HaskewLayton et al., 2008).

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4.2 Volume Sensitive Channels Release of amino acids out of cells suffering from hypoosmotic shock was first described in 1988-1990 for the culture of cortical astrocytes (Kimelberg et al., 1990; Pasantes-Morales, and Schousboe, 1988; Pasantes-Morales et al., 1990). It was shown that the majority of organic osmolytes have been transported not involving energy-dependent carrier proteins (Kimelberg, 1995). Modulation of osmosensitive chloride transport and transport of organic osmolytes by the same pharmacological agents put an idea of using of identical transport pathways (Sanchez-Olea et al., 1996). Activation of volume-sensitive anion channels permeable for amino acids by hypotonic swelling has been described in many cell types (Junankar and Kirk, 2000). In MDCK and glioma cells it was recorded the current through volume-sensitive chloride channels and suggested to be caused by glutamate, taurine, glutamine, glycine (Roy, 1994). Using C6 glioma cell it was demonstrated that volumesensitive release of various substances such as taurine and inositol has been occurred via a common transport system (Jackson and Strange, 1993). Channels described in astrocytes can pass a number of organic osmolytes such as amino acids, polyols, polyamines and other compounds with a radius of molecules close to the radius of a molecule of glutamate (Junankar and Kirk, 2000). It has been suggested that glutamate and basic amino acids are released during cell swelling using these channels termed "volume sensitive osmolyte anion channels" (VSOAC) (Strange and Jackson, 1995; Basavappa et al., 1996, Pasantes – Morales et al., 1994). Accordingly, blockade of glutamate release by pharmacological inhibition of VSOAC activity can significantly reduce the infarct size following focal cerebral ischemia (Zhang et al., 2008). However, data concerned involvement of VSOAC into glutamate release in neurons are spare. Contribution of osmolyte leak pathway into amino acid release from cortical synaptosomes, estimated by the influence of Cl channel blocker NPPB, was shown in the work of Tuz and co-workers (Tuz et al., 2004) and comprises up to 55% for taurine, but only 10-18% for GABA, with apparently no contribution for glutamate. It was suggested that in presynaptic area anion channel route is predominantly used for taurine efflux. While glutamate and GABA respond to osmotic shock by neurotransmitter-like mechanism. These data are consistent with the results of Levko and co-authors (Levko et al., 2004), who proved an absence of effect of anion channel inhibitors, such as DIDS, niflumic acid and tamoxifen on release of glutamate and GABA caused by hypoosmotic shock of synaptosomes. Although both astrocytes and neurons, when maintained in culture, are observed to swell in response to osmotic stress, glial cells make the major contribution to volume regulation in the CNS in vivo (Kimelberg 1995). As a consequence, their involvement in osmolyte release has been extensively documented (Mongin and Kimelberg 2002, 2005; Pasantes-Morales et al., 2006). It was shown that both hypotonic and ischemic stimuli caused the release of glutamate from cultured mouse astrocytes by virtue of two channels, volume-sensitive outwardly rectifying (VSOR) anion channel and maxi-anion channels, jointly represent a major

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conductive pathway for the release of glutamate from swollen and ischemia-challenged astrocytes, with the contribution of maxi-anion channels being predominant (Liu et al., 2006). Moreover, no contribution of gap junction hemichannels, vesicle-mediated exocytosis, or reversed operation of the Na-dependent glutamate transporter was determined in this work. There are a number of other reports supporting maxi-anion channels and VSOAC channelbased mechanism of release of glutamate from astrocytes upon ischemic and osmotic stress conditions (Pangrsic et al., 2006; Liu et al., 2006). Consistent with the involvement of volume regulated anion channels, in the rat brain in vivo it was clear showed that hypoosmotic medium-induced release of the excitatory amino acids was inhibited by the anion channel blocker DNDS, but not by the glutamate transporter inhibitor TBOA or Cd2+, which inhibits exocytosis. Furthermore, swelling-induced excitatory amino acid release was not blocked by inhibitors of two alternative glutamate and aspartate release pathways, i.e. reversal of glutamate transporters and exocytotic release. (HaskewLayton et al., 2008).

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4.3 Transporter Reversion It was hypothesized that reverse mode operation of amino acid transporters, located on neuronal and glial cell membranes, might be responsible for extruding of appropriate neuroactive osmolyte under the osmotic shock. Indeed, there is evidence concerning participation of glutamate and GABA carriers in hypoosmolarity induced release from cortical synaptosomes, where TBOA and NO-711 resulted in 37 and 28% reduction of glutamate and GABA efflux, respectively (Tuz et al., 2004). However, in hemisphere synaptosomes, application of 2,4-L-trans-PDC has not attenuated glutamate release induced by hypoosmotic shock (Waseem et al., unpublished data). On experiments of cerebral cortex, swelling induced by ischemic conditions was sensitive to glutamate transporter inhibitor DL-threo-TBOA. It was indicated that extracellular Ca2+independent reversed transport, primarily from glial cells by the EAAT 2 carrier, is responsible for a substantial (42 and 56%) portion of the increase in extracellular glutamate and aspartate levels, respectively (Phillis and O'Regan, 2000; Phillis et al., 2000; Nishizawa, 2001). In astrocytes a reduction in the uptake mechanisms for amino acids has also been reported to participate in their osmolarity-induced efflux, although its contribution was observed to be minimal (Kimelberg et al., 1995). It has been confirmed that swelling-induced excitatory amino acid release from astrocytes culture and from cortex was not blocked by inhibitor glutamate transporters TBOA (Haskew-Layton et al., 2008).

4.4 Reuptake of Glutamate It was shown that reduction of medium osmolarity led to substantial inhibition of glutamate and GABA transporting systems in presynaptic nerve terminals (Waseem et al., 2004). These data have been confirmed by finding that uptake of D-aspartate into SH-SY5Y

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cells is markedly attenuated by hypoosmolarity after stimulation by mAChR activation (Foster et al., 2010). Suppression of reuptake systems represents an additional still underestimated pathway of developing pathological conditions upon brain cell swelling. As increased, due to a blockade of transporters, extracellular concentration of neuronactive substances will worsen conditions of neighboring cells suffering on enhanced excitotoxic release of glutamate of GABA.

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5. HYPERTONICITY INDUCED GLUTAMATE TRANSPORT In 1952 it was discovered that neurotransmitters are released by small portions at fusing synaptic vesicles with plasma membrane of presynaptic terminal. This process was called vesicular release or in another word  exocytosis (Fatt and Katz, 1952; Heuser and Rees¢, 1981; Del Castillo and Katz, 1956). Initially, the process of exocytose was considered to be external calcium dependent. Further it was well documented that hypertonic shrinking, inhibition of casein kinase II and ruthenium red are able to induce vesicular release of neurotransmitter without involving calcium (Rosenmund and Stevens, 1996; Trudeau et al., 1996; Ashton et al., 2001; Rizzoli and Betz, 2002). Several signaling processes transduce cell stretch to exocytosis including changes in cytoskeleton, activation of integrins, phospholipases, tyrosine kinases and cAMP (Hamill and Martinac, 2001; Apodaca, 2002; Grinnell et al., 2003). It was assumed that hypertonic stimulation circumvented the normal dependence of vesicle fusion on calcium ions, presumably through a mechanical lowering of the energy barrier for membrane fusion (Rosenmund and Stevens, 1996). Further, for hippocampal synapses, it was reported that when exocytosis is produced by hypertonic solution, a fraction of the exocytose events occur in a calcium-independent ‘‘kiss and run’’ mode (Stevens and Williams, 2000). At Drosophila frog neuromuscular junctions, mechanical tension on integrins due to muscle stretch or hypertonicity causes a powerful modulation of release efficacy. Hypertonicity, studied in both frog and Drosophila terminals, causes a spontaneous release, which was also Ca2+-independent and mostly dependent on integrins (Suzuki et al., 2002; Grinnell et al., 2003). On the contrary, at central nervous system synapses it appeared to be unlikely that integrins take part in hypertonicity induced neurotransmitter release. Blocking of these protein complexes has not prevented glutamate release form nerve terminals (Waseem et al., 2008). In general, glutamate released upon hypertonicity-induced nerve terminal shrinking can lead to the pathological conditions similar to those observed under swelling.

CONCLUSION Cells have to regulate their volume in order to survive. Moreover, it is now evident that cell volume per se and the membrane transport processes which regulate it, comprise an important signalling unit. For example, macromolecular synthesis, apoptosis, cell growth and hormone secretion are all influenced by the cellular hydration state. The release of neurotransmitters can have both deleterious and protective effects in the surrounding

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tissue/organ environment by regulating cell volume or by activation of other signaling process leading to cellular death, proliferation or differentiation which strengthens their physiological importance. Therefore, a thorough understanding of volume-activated transport processes could lead to new strategies being developed to control the function and physiology of both neuronal and glial cells. Despite being the subject of intense research interest, the nature of the volume-activated glutamate efflux pathway is still a matter of controversy. On the one hand it has been suggested that osmosensitive glutamate efflux utilizes volume-sensitive anion channels whereas on the other it has been proposed that exocytosis and transporter reversion are involved in. Taken together, available findings indicate that different transport mechanisms and/or distinct cellular sources mediate hypoosmotic medium-induced release of the glutamate in vivo.

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Chapter 4

GLUTAMATE: A GLOBAL REGULATOR Santanu Palchaudhuri1 and Dhrubajyoti Chattopadhyay23 1

Albert David Ltd, 5/11 D. Gupta Lane, Kolkata – 700050, West Bengal, India 2 3 Department of Biochemistry and Department of Biotechnology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata - 700019, West Bengal, India

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ABSTRACT Glutamate has long been recognized as a major excitatory neurotransmitter in mammalian central nervous system (CNS) and is required for normal brain activities such as learning and memory. Its functions are mediated by glutamate receptors (Ionotropic and Metabotropic), transporters (present on the cell surface or in vesicles) and various other signaling molecules. Interestingly, glutamate receptors and/or transporters have also been found in several non-neuronal cell types, both inside and outside CNS. These include astrocytes in CNS and other tissues such as bone, heart, skin, gastrointestinal tract, pancreas, liver, lung, testis, adrenal/pituitary/pineal glands, megakaryocytes, platelets, thymocytes and lymphocytes. Functional glutamate signaling has been found in plants as well. Together, these suggest a more global role for glutamate as an extracellular signaling molecule involved in various physiological processes. However, although the physiological role for glutamate is well established in CNS, the same is not true for other non-neuronal cell types. This review summarizes the current knowledge on glutamatergic signaling in both neuronal and non-neuronal cell types with emphasis on chemoattraction.

INTRODUCTION Glutamate is the major excitatory neurotransmitter in the mammalian Central Nervous System (CNS), acting through both ionotropic receptors such as AMPA, NMDA and Kianate receptor, and G-protein coupled metabotropic receptors [1-15]. The glutamate mediated signaling events in CNS are essential for synaptic development, memory and learning, which play a very critical role in brain development [16-22]. In addition to its presence in the

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excitable neurons, glutamate receptors are also expressed in different types of non-excitable glial cells in the CNS that includes astrocytes, oligodendrocytes, and microglia [2, 23]. Glutamate signaling in glial cells has been found to be very important for their function as well as their interaction with neurons, which presumably affect memory or cognition. Apart from its role as neurotransmitter, glutamate could also act as neurotrophic factor during CNS development [24, 25]. Subsequently, activation of metabotropic glutamate receptors was shown to stimulate DNA replication and activate mitogen-activated protein kinases in astrocytes [26]. Recently, glutamate has been shown to exhibit neuroprotective and immunomodulatory functions as well. Elevated level of glutamate is a hallmark of the autoimmune neurological diseases like multiple sclerosis. Previously, this excess glutamate was suggested to contribute to neurotoxicity leading to the disease phenotype. Now, Fallarino et al [27] have shown that this extracellular glutamate can activate a metabotropic glutamate receptor, mGluR4, expressed on dendritic cell surface, which in turn, drives a regulatory T cell response that can inhibit the development of autoimmunity and protect from neuroinflammation in a mouse model of multiple sclerosis. Taken together, it is clear that glutamate signaling can exert a wide range of effects on the development and functioning of mammalian nervous system. Consequently, various glutamate receptor dysfunctions are found to be associated with neurological disorders such as epilepsy, ischemic brain damage, Parkinson’s disease, Alzheimer’s disease, Huntington’s chorea and amyotrophic lateral sclerosis. Although Glutamate signaling has long been assumed to be restricted to the central nervous system, a growing body of evidence now documents that non-neuronal cells including bone osteoblasts, keratinocyte, cells of pancreas, testis, taste buds, liver, lung, kidney, intestine, esophagus, adrenal, pituitary and pineal glands, heart, Megakaryocytes and their precursors in the bone marrow, lymphocytes, neutrophils etc also possess glutamate signaling components such as receptors and/or transporters [28-50]. The physiological significance of the presence of glutamate signaling in non-excitable cells in these peripheral tissues remains largely elusive. However, one key aspect seems to be the regulation of cellular differentiation in these tissues. For example, glutamate signaling has been strongly implicated in bone development [51-54]. Bone-forming osteoblast and bone-resorbing osteoclast cells are known to act together to regulate bone formation and maintenance. A balance between these two cell types is very crucial, as any imbalance could lead to metabolic bone diseases such as osteoporosis, Paget’s disease and osteopetrosis. In this scenario, glutamate is slowly emerging as one of the factors involved in the intercellular communication between bone cells as well as for their differentiation and functioning. Interestingly, glutamate signaling has also been implicated in epidermal renewal [38]. It was shown that various skin cell types, including keratinocyte, express several classes of glutamate receptors and/or transporters. Changes in the distribution of these factors were observed during re-epithelization of skin wound as well as during embryonic epidermal development indicating a role for glutamate in epidermal renewal and wound healing process. Additionally, pancreatic islet cells were also found to express ionotropic glutamate receptors that modulate insulin secretion [55-57]. Glutamate was further shown to improve gastric digestive function by modulating gastric secretions, mucosal protective factors and motility. A variety of other roles has also been suggested for metabotropic glutamate receptors such as controlling hormone production in the adrenal gland and pancreas, regulating mineralization in the developing cartilage, modulating lymphocyte cytokine production, directing the state of

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differentiation in embryonic stem cells etc. Notably, glutamate signaling has also been observed in various tumor types, where glutamate regulated both the tumorigenesis and metastasis processes. Notably, glutamate and other neurotransmitters, such as norepinephrine, dopamine and GABA have been shown to act as extracellular signaling cues and regulate the cell migration process. Cell migration is highly regulated, multistep process that plays a central, essential role in a wide variety of biological phenomena including embryonic development, organogenesis, tissue repair and regeneration, and also in progression of diseases such as cancer, mental retardation, atherosclerosis, and arthritis [58, 59]. During embryogenesis, cell migration plays a very crucial role in various morphogenic processes such as gastrulation and nervous system development. Migration of cells from the neural crest is one of the best studied embryonic migrations. These cells originate from the top of the neural tube and migrate to a wide variety of target sites including bone, cartilage and skin. Cell migration continues to contribute towards various physiological processes in the adult organism as well. For example, during the inflammatory response, various cell types including the leukocytes immigrate into the areas of insult to mediate phagocytic and immune functions. Cell migration plays a very important role during wound healing as well. Fibroblasts and vascular endothelial cells migrate along with leukocytes towards the wound during the repair process. Notably, cell migration is also utilized under various pathologic conditions. For example, in cancer metastasis, tumor cells leave the primary mass and migrate into the circulatory system. Subsequently, these cells again leave the circulation and migrate to a new site, where they colonize and form the secondary metastases. In cases of chronic inflammatory syndromes, such as asthma, rheumatoid arthritis, multiple sclerosis, psoriasis and Crohnƍs disease, continuous infiltration/migration of immune cells into abnormal target tissues leads to their activation causing massive damage and progressive deterioration of the tissue. Importantly, in most of the above mentioned situations of cellular migration, the amino acid glutamate has been shown to play a very important and essential role (Figure 1). It has shown to regulate brain development and functioning by controlling migration of both excitable neurons as well as non-excitable glial cells. In the peripheral tissues also, it was found to regulate cell migration among other functional processes.

Figure 1. Physiological significance of glutamate signaling. Glutamate: Functions, Regulation and Disorders : Functions, Regulation and Disorders, Nova Science Publishers, Incorporated, 2012. ProQuest

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For example, glutamate was found to control T cell and neutrophil migration that might have implications for inflammation and/or wound healing. In addition, glutamate was also demonstrated to modulate tumor cell migration, invasion and even metastasis. In this review, we discuss the physiological significance of glutamate mediated regulation of cell migration in neuronal cells and beyond.

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GLUTAMATE MEDIATED CELL MIGRATION IN CNS In the developing brain, proper migration and placement of immature neurons (neuroblasts) from the site of origin to the target location in designated areas of brain is absolutely essential for the construction of functional synaptic circuitry in the brain. Although the majority of the neuronal migration occurs during the embryonic period, a significant proportion of neurons also migrate after birth. Principally two different modes of migration have been observed during brain development: (1) a radial, glial-guided mode of migration for the principal neuronal cells, and (2) a tangential mode of migration for the interneurons. Radial migration is characterized by close interactions between migrating neurons and the processes of radial glial cells, which form a scaffold bridging the proliferative ventricular zone and pial surface. For example, in the cerebral cortex, post mitotic neurons migrate from the ventricular zone towards the pial surface to reach the top of the cortical plate, where their migration terminates and they assemble into layers with distinct patterns of connectivity. Furthermore, radial migration of cortical neurons can occur in two distinct modes, somal or nuclear translocation and locomotion. During somal translocation neurons first extend a long, basal process from the ventricular zone and attach the leading edge to the pia. This is followed by rapid nucleokinesis, a process by which the nuclei as well as soma of a bipolar cell is transported towards the leading end of the cell, and shortening of the basal process. Locomoting neurons do not extend the length of their leading process as cell soma and the leading edge travel together. As the leading edge is anchored at the pial surface, neurons migrating by somal translocation are less dependent on glia. Locomotion of neurons, on the other hand, absolutely requires presence of guiding radial glial cells. Besides the radial migration, subsets of neurons also migrate in a tangential manner. During tangential migration neuronal cells do not interact with radial glial cell processes, unlike the radial migration. Neurons that eventually become pyramidal or glutamatergic cortical neurons tend to migrate radially, whereas GABA (Ȗ-aminobutyric acid)-containing interneurons migrate tangentially. Interestingly, neurons can switch dynamically between tangential and radial modes of migration, as has been observed in cortical interneurons as well as in cerebellar granule interneurons. The switch from a tangential to a radial mode of translocation is not unique to cortical interneurons or cerebellar granule neurons, and has also been observed for spinal cord dorsal column neurons and is probably a basic property of migrating inhibitory interneurons. As they migrate throughout the cerebral tissue, immature neurons or neuroblasts are influenced by several factors that modulate their journey. Among these modulators, transmitters have been shown to play an important role. Indeed, several studies have led to the conclusion that transmitters such as glutamate have an essential regulatory effect on migrating neuroblasts [60-65] (Figure 2).

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Figure 2. Glutamate mediated regulation of cell migration in CNS.

Glutamate and Cerebellar Granule Cell Migration: The first evidence of glutamate having a modulatory role in neuronal migration was provided by Komuro and Rakic [65] for granule cell migration in the cerebellum. Newly born granule cells in the developing cerebellum traverse the expanding molecular layer and the adjacent Purkinje cell layer to reach their final destination in the internal granular layer (IGL). Komuro and Rakic [65] showed that in postnatal rat cerebellar slice preparations granule cell migration was inhibited by ionotropic glutamate receptor antagonists, suggesting that glutamate might have neuronal cell migration inducing ability. Notably, a number of extracellular ligands including growth factors [66], lysophosphatidic acid [67] and neurotransmitters such as acetylcholine [68] and glutamate [69] was known to be able to induce Ca2+ oscillations. Consequently, it was shown that glutamate-mediated Ca2+ oscillation in cerebellar granule cells is absolutely required for neuronal migration [70]. Here, the activation of NMDA receptor caused the transient influx of Ca2+ which in turn regulated the rate and velocity of granule cell migration [71]. Kim et al, [72] further shed light on the mechanism of granule cell migration mediated by glutamate. The authors showed that at first, glutamate activated the AMPA receptor on Bergmann glia, leading to phosphorylation of the receptor and consequent release of receptor bound glutamate receptor interacting protein (GRIP). The dissociated GRIP then binds and activates Serine Racemase, which in turn converts L-Serine to D-Serine. This newly synthesized DSerine is then released and along with glutamate activated the NMDA receptor on cerebellar granule cells, thereby, releasing intracellular Ca2+ and enhancing the migratory ability of the granule cells. Glutamate and Embryonic Cortical Neuron Migration: Behar et al [64] demonstrated that glutamate can induce migration of mice embryonic cortical neurons from developing cortex to the cortical plate by activating NMDA receptor. The glutamate stimulated migration was inhibited by NMDA receptor antagonists, MK-801 and APV. Glutamate and GnRH neuron migration: Migration of gonadotropin releasing hormone (GnRH) neurons was also found to be regulated by glutamate [62]. GnRH neurons are born outside the brain in the olfactory placode and migrate tangentially through the nasal septum to reach the forebrain and, ultimately, the hypothalamus during embryogenesis [73-75]. Simonian and Herbison [62] showed that both AMPA and NMDA receptors have a distinct, spatially restricted role in the tangential migration of GnRH neurons. Their work revealed that the migration of GnRH neurons from nose to brain depends upon the glutamate mediated activation of AMPA receptors. However, within the forebrain glutamate slowed down the migration of GnRH neurons by activating NMDA receptor. This was a very unique situation, since glutamate mediated activation of different receptor types separated both temporally and spatially, yielded contrasting outcome.

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Glutamate and Migration of Hippocampal Interneurons: Glutamate was further found to regulate migration of hippocampal interneurons by activating AMPA receptors [76, 77]. Migrations of pyramidal neurons and GABAergic interneurons were found to be interdependent. Glutamate released from glutamatergic neurons facilitated the migration of hippocampal GABAergic interneurons. In turn, the interneurons would release GABA, facilitating the migration of glutamatergic neuroblasts. Glial Cell Migration and Glutamate: In addition to the excitable neurons, migration of the non-excitable glial cells present in the CNS is also regulated by glutamate. For example, NMDA receptor activity is required for the long-distance migration of the oligodendrocyte precursor cells, which is essential for myelin formation. The active NMDA receptor is necessary for the expression of the highly sialylated polysialic acid-neural cell adhesion molecule (PSA-NCAM), which in turn, is required for their migration [78]. Oligodendrocyte progenitor cells have also recently been shown to activate AMPA receptor as they migrate [79]. Glutamate binding to AMPA receptor stimulated formation of an alpha v integrin/ myelin proteolipid protein (PLP)/AMPA receptor protein complex that reduced cellular binding to the extracellular matrix thereby enhancing oligodendrocyte progenitor cell migration. Furthermore, AMPA was found to stimulate oligodendrocyte progenitor migration by increasing both the rate of cell movement and the frequency of Ca2+ oscillation [79]. Although both the AMPA and NMDA receptors were found to be functional and necessary for the migration of the oligodendrocyte precursor cells, it is still not clear, whether they are activated simultaneously, or are separated temporally and/or spatially. Glutamate Transport and Glia – Neuron Cross-Talk: It should be noted that the majority of the glutamate present in the brain, is produced by astrocytes. Moreover, the astrocytes were shown to release cytosolic glutamate store in response to molecules such as prostaglandin E2, ATP, bradykinin and even to glutamate itself, in a calcium dependent manner [80-84]. Potentially, this can further activate the astrocytes themselves as well as the neighboring neuronal cells, thus causing astrocytes and neurons to cross-talk. Indeed, it has been demonstrated that astrocytes can respond to synaptic activation [85] and that they can modulate synaptic neurotransmission by releasing glutamate in a Ca2+ - dependent manner [86, 87]. Indeed, Platel et al., [88] recently found that astrocyte to neuroblast glutamate signaling in the neurogenic subventricular zone (SVZ)/rostral migratory stream region (RMS) regulates the NMDA receptor activity in neuroblasts. This glutamate mediated activation of NMDA receptors critically controls the number of neurons that ultimately reach the olfactory bulb and are available to integrate into the existing synaptic network. Based on the above discussion, it is conceivable that, when these neuronal migration promoting signals are absent or incorrect, neurons end up being at the wrong place at the wrong time. This could result in structurally abnormal or missing areas in brain in the cerebral hemispheres, cerebellum, brainstem, or hippocampus, leading to the development of Neuronal Migration Disorders (NMDs) [89, 90], a group of birth defects caused by the abnormal migration of neurons in the developing brain and nervous system. The structural abnormalities found in NMDs include schizencephaly, porencephaly, lissencephaly, agyria, macrogyria, polymicrogyria, pachygyria, microgyria, micropolygyria, neuronal heterotopias (including band heterotopia), agenesis of the corpus callosum, and agenesis of the cranial nerves.

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GLUTAMATE MEDIATED CELL MIGRATION IN PERIPHERAL TISSUES Although, presence of various components of glutamate signaling pathway has been observed in different peripheral tissues, their physiological significance is still not very clear. Few studies have revealed that several neurotransmitters and neuropeptides including dopamine, somatostatin, substance P, calcitonin- gene-related peptide, neuropeptide Y, and GnRH I and II were able to stimulate their corresponding receptors expressed on the T cell surface and trigger various T cell functions including de novo gene expression, cytokine secretion, integrin-mediated adhesion, in vitro chemotactic migration, and in vivo homing to specific organs. The first study describing the presence of ionotropic glutamate receptors in human T lymphocytes was reported in 2001 by Lombardi et al [35]. The authors demonstrated presence of functional NMDA, AMPA as well as KA receptors in human lymphocytes by examining glutamate mediated potentiation of phytohemagglutinin (PHA)-or anti-CD3 antibody induced intracellular calcium rise. Two years later, Ganor et al. [91], demonstrated that glutamate could activate AMPA receptor subtype 3 (GluR3) and trigger a key T cell function, the integrin-mediated adhesion to laminin and fibronectin (FN). The glutamate mediated cell adhesion was blocked by AMPA receptor antagonist CNQX and NBQX. Pacheco et al. [92] later showed that this glutamate mediated cell adhesion is accompanied by inhibition of IL-10 production. Interestingly, glutamate was also found to significantly up-regulate the chemotactic migration of T cells toward the stromal cell-derivedfactor-1Į chemokine (SDF-1Į), also known as CXC chemokine ligand-12 (CXCL12) [91]. Ganor et al [93] further showed that glutamate, via AMPA-GluR3, may activate only resting, but not TCR-activated human T cells, which do not express the receptor on their surface. Importantly, CXCL12 is constitutively expressed both in the periphery and in the nervous system and plays a key role in numerous immune and neuronal functions. It is therefore possible that CXCL12/SDF-1 and glutamate may act in concert and recruit T cells to specific sites, in the nervous and immune systems. In addition, study from our lab showed that glutamate can act as a novel chemotaxisinducing factor for human neutrophils [50]. The glutamate mediated chemotaxis was accompanied by polymerization of F-actin. Additionally, glutamate was also found to induce actin cytoskeleton polarization suggesting increase in migratory phenotype in human neutrophils. This was further supported by the observation that in response to a glutamate gradient, human neutrophils became polarized. Further work revealed that class I metabotropic Glutamate receptors, mGluR1 and mGluR5, along with Integrin ȕ2 receptor (ITG ȕ2) LFA-1 play a very crucial role in transducing Glutamate mediated signaling events in human neutrophils (Palchaudhuri et al, unpublished data). Importantly, neutrophils are one of the first few cell types arrive at the site of infection or wound and plays a key role in fighting the invading microorganisms and/or healing wounds. Moreover, high level of glutamate has been found in wound fluid [94]. Taken together, it is therefore possible that following an infection or injury, glutamate is released from the damaged cells and/or nerve endings present at the site of inflammation and/or damage, into the extracellular space. This in turn can draw various cell types including neutrophil towards the infected/injured site.

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GLUTAMATE MEDIATED CELL MIGRATION IN CANCER The primary cause of death in cancer patients is metastasis: spreading of tumor cells from its primary site to a distant secondary site (s). In general, metastasis is known to involve a cascade of events and completion of all of them is required for the growth of tumor cells at the secondary site [95-97]. At the beginning, cells within primary tumor lose cell-cell and cell-matrix contacts, detach, migrate and invade stromal tissue and enter into the circulatory blood system (intravasation). Once in the circulation, the tumor cells undergo capillary bed arrest until they extravasate into surrounding tissues, migrate and invade to a new site, attach and proliferate to form micrometastases. These events suggest that tumor cell adhesion, migration and invasion in and out of the extracellular matrix (ECM) play a very important role in spreading of the disease in an individual. Glutamate Signaling and Cancer Cell Migration: Significantly, emerging evidences point to the fact that tumor growth, invasion, and metastasis are regulated by neurotransmitters that bind to serpine receptors, such as dopamine, somatostatin, substance P, calcitonin generelated peptide, neuropeptide Y, as well as glutamate. Among these, glutamate was found to be an important regulator of tumor cell proliferation and migration. In 2001, Rzeski et al first demonstrated that glutamate antagonists inhibited the proliferation of human tumor cells [98]. They found that the NMDA antagonist dizocilpine mostly affected colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells. On the other hand, breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells were largely sensitive to the AMPA receptor antagonist GYKI52466. Moreover, they showed that glutamate antagonists reduced migration and invasion of cancer cells. Tumor cells treated with NMDA and AMPA antagonists exhibited much less membrane ruffling and fewer pseudopodial protrusions compared to the untreated ones. Furthermore, motility of lung carcinoma, rhabdomyosarcomay medulloblastoma, and thyroid carcinoma cells exposed to NMDA or AMPA antagonists were found to be greatly reduced compared to the control cells. Glutamate was further found to regulate oral carcinoma cell migration [99]. An mGluR5 agonist, DHPG, was shown to increase tumor cell migration, invasion, and adhesion in HSC3 oral tongue cancer cells. In contrast, the mGluR5 antagonist MPEP inhibited these properties. Notably, Choi et al [100] had previously shown that increased expression of the glutamate receptor subunit NMDAR1 correlated significantly with tumor size, lymph node metastasis and cancer stage of oral squamous cell carcinoma. Glutamate signaling was also identified in melanomas. Le et al demonstrated that the glutamate-release inhibitor Riluzole or the noncompetitive metabotropic glutamate receptor-1 (GRM1) antagonist BAY 36-7620 was able to inhibit GRM1-expressing melanoma cell migration, invasion and proliferation [101]. Furthermore, ectopic expression of mGluR1 in human normal melanocytes, which normally lack this receptor, resulted in enhanced proliferation and transformation of melanocytes into malignant tumors that caused formation of distant metastases [102, 103]. Ripka et al further found involvement of functional glutamate signaling in pancreatic cancer progression. The authors demonstrated that glutamate receptor inhibitors such as GYKI52466 and SYM2206 significantly decreased survival of pancreatic cancer cells [104]. They identified GRIA3, an AMPA receptor to play a crucial role in pancreatic carcinoma progression. It was found that overexpression of GRIA3 significantly reduced apoptosis and enhanced both proliferation and tumor cell migration, whereas, knock-down of GRIA3 significantly reduced proliferation and

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migration and enhanced apoptosis in pancreatic cancer cells. Interestingly, an opposing view of glutamate as a positive regulator of tumor cell migration was observed by Wu et al (2009). The authors proposed that GRIK2, a gene belonging to the kainate receptor subgroup of the ionotropic glutamate receptor family, is a novel tumor-suppressor gene in gastric cancer and suppress cell migration. In addition, expression of mGluR4 was observed in medulloblastoma and was shown to be inversely correlated with tumor progression, spreading and recurrence [105]. Glutamate Transport and Tumor Cell Migration: Recently, Stepulak et al. [106] demonstrated that glutamate receptors are expressed in a variety of cancer cell lines (of neuronal and non-neuronal origin) and tumors, such as, glioma, colorectal and gastric cancer, oral squamous cell carcinoma, prostate cancer, melanoma and osteosarcoma. Moreover, the metabolic properties of tumors combined with altered metabolism in patients with cancer contributed to abnormally elevated glutamate plasma concentrations in these patients [107]. This extracellular glutamate is likely to activate its receptors present in cancer cells and trigger intracellular signaling pathways, which may affect growth, survival and proliferation of these cells [106]. Notably, release of glutamate from cancer cells into the ECM is emerging as a common biological feature rather than being specific to CNS tumor cell types [108]. Astrocytic tumors were found to release glutamate at high levels which has been shown to enhance tumor proliferation and invasion. Seidlitz et al [109] showed that several cancer cell lines also released signi¿cant quantities of glutamate into their extracellular environment and that this release may be sensitive to media cystine levels. Importantly, these cells express the proteins for functional NMDA type glutamate receptor subunits both in vitro and in vivo. Furthermore, previous studies have showed that the gene for the catalytic subunit of system xc- (xCT or SLC7A11) is expressed, and potentially upregulated in particular cancer cell types [110, 111]. The system xc- is a glutamate/cystine antiporter, exchanges one molecule of intracellular glutamate for one molecule of extracellular cystine and functions primarily as a means of accumulating intracellular cystine for the subsequent synthesis of glutathione, the primary antioxidant in many cells. Cancer cells require high levels of glutathione to counteract the oxidative stress arising from their increased metabolic rate. Sharma et al [112] also recently have shown that a number of cancer cell lines, regardless of their tissue of origin, expressed xCT. Chen et al [113] further showed importance of the glutamate transport system in the esophageal cancer. The authors showed that disruption of xCT by an inhibitor, sulfasalazine, or by xCT siRNA in an esophageal cancer cell line KYSE150, enhanced homotypic cell-cell adhesion and attenuated cell-extracellular matrix adhesion. Sulfasalazine significantly inhibited both in vitro cell invasion of KYSE150 and its experimental metastasis in nude mice. It was found that absence of xCT caused upregulation of Caveolin-1. This, in turn, inhibited the beta-catenin transcriptional activity by recruiting it to the plasma membrane. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species (ROS) - induced p38 MAPK activation [113]. Ye and Sontheimer [114] also showed that system xc- is the principal protein responsible for glutamate release from glioma cells. Potentially, this released glutamate can act on the cell of origin as well as other neighboring cells, therefore, creating an autocrine/paracrine positive loop (Figure 3).

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Figure 3. Autocrine and/or paracrine signaling mediated by glutamate regulates tumor cell malignancy.

Indeed, it was found that glutamate released from glioma cells acts as an essential autocrine/paracrine signal that promotes glioma cell invasion [115]. Specifically, chemotactic invasion and scratch wound assays each showed dose-dependent inhibition of cell migration when glutamate release was inhibited using either S-(4)-CPG or sulfasalazine, both potent blockers of system xc-. Moreover, addition of exogenous glutamate in the continued presence of the inhibitors could be able to overcome this inhibition. Migration/invasion was also inhibited when Ca2+- permeable AMPA receptors were inhibited by GYKI or Joro spider toxin. Ca2+ imaging experiments showed that the released glutamate activates Ca2+permeable AMPA receptors and induces intracellular Ca2+ oscillations that are essential for cell migration. This was in line with the previous observations of Ishiuchi et al, who showed that activation of Ca2+ -permeable AMPA receptors induced migration and proliferation of human glioblastoma cells [116]. It was further shown that Ca2+ -permeable AMPA receptors activated Akt, which in turn facilitated proliferation and motility of glioblastoma cells [117]. Notably, the Ca2+ -permeable AMPA receptors lack the GluR2 subunit which is required to prevent Ca2+ permeation [118]. To demonstrate a role for these receptors in glioma migration and point to the importance of glutamate mediated induction of Ca2+ entry in the process, Ishiuchi et al. [116] introduced the GluR2 subunit into glioma cells, which rendered glioma cells unable to respond to glutamate with Ca2+ oscillations. Importantly, upon implantation into a host animal brain these glioma cells expressing GluR2 failed to invade. Notably, Lyons et al [115] also found that treatment of SCID mice with sulfasalazine significantly reduced tumor invasion. Interestingly, in gradient chambers, glioma cells migrated toward elevated Glutamate concentrations, suggesting that Glutamate could be considered as a chemoattractant. It was further shown that overexpression of GluR1, the most abundant subunit of the AMPA receptor in glioma cells, resulted in an increase in glioma adhesion to extracellular matrix (ECM). The enhanced adhesion to the ECM was found to be mediated via increased surface expression of ȕ1integrin and subsequent activation of focal adhesion kinase (FAK). Furthermore, stimulation of the AMPA receptor with Glutamate or AMPA induced cellular detachment mediated through Rac1 and caused an increase in transwell migration in vitro and an increase in tumor invasion in vivo [60]. In addition to promoting collective cell migration in glioblastoma cells, the released extracellular glutamate also caused widespread excitotoxic death of peritumoral neurons [114]. It was proposed that this form of excitotoxic neuronal cell death allowed the tumor to proliferate into the vacated space [119]. Importantly, this could also create a more permeable space through which a migration/invasion process can occur.

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CONCLUSION

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Components of the glutamate signaling pathway such as glutamate receptors and transporters are expressed in a wide variety of cell types in mammals. These include the excitable neuronal cells as well as the non-excitable cells such as the glial cells in CNS and cells from various peripheral tissues. One of the most important physiological functions of glutamate signaling in these cell types is regulation of cell migration. Glutamate was found to regulate migration of immature neuronal cells to their correct target location that help them to position at the designated site and form synapses necessary for their function. Additionally, during inflammation and wound repair, glutamate was found to modulate migration of neutrophils as well as keratinocytes, thereby facilitating the wound healing process. Glutamate was also shown to potentiate T cell migration towards CXCL12. Furthermore, glutamate was found to regulate tumor cell migration. Indeed, glutamate was demonstrated to promote migration, invasion and even metastasis in cancer cells of different tissue origins. This phenomenon is now being considered as the general property of cancer cells. If holds true, this might give us the opportunity to explore new therapeutic targets in the glutamate signaling pathway. Interestingly, glutamate signaling was also suggested to negatively regulate cancer cell migration in a few instances. Clearly, further studies are required to explain this apparent contradiction. It should also be emphasized that glutamate signaling was found to function as an autocrine/paracrine system across various tissue types, both under normal physiological and disease conditions, and regulate a wide range of cellular processes. Taken together, these suggest a global role for glutamate as a critical signaling intermediate regulating a wide range of physiological events.

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Chapter 5

CALCIUM-CALMODULIN KINASE TYPE II-MEDIATED GLUTAMATERGIC PLASTICITY UNDERLIES EXPRESSION OF BENZODIAZEPINE-WITHDRAWAL ANXIETY Elizabeth I. Tietz1, 2 and Damien E. Earl1 1

2

Departments of Physiology and Pharmacology and Neurosciences, University of Toledo College of Medicine, Toledo OH, 43614, U. S.

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ABSTRACT Prolonged treatment with CNS depressant drugs, such as the benzodiazepine antianxiety drugs increases the possibility of physical dependence manifested as withdrawal anxiety. While benzodiazepines have their anxiolytic, hypnotic and anticonvulsant actions via allosteric potentiation of GABA-A receptor function, during drug withdrawal modulation of excitatory – Į-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in hippocampal CA1 neurons is closely coupled to the expression of drug-withdrawal anxiety. Electrophysiological and immunochemical studies of rat CA1 neurons and minislices during withdrawal from 1-week oral flurazepam administration point to increased synaptic insertion of GluA1 homomeric AMPARs as a critical link in the behavioral expression of anxiety. The mechanism underlying drug-induced AMPAR potentiation during benzodiazepine withdrawal is analogous to electrical stimulus-induced long-term potentiation of hippocampal CA1 afferents, and involves a two-step process: insertion of GluA1 homomeric receptors followed by calcium-calmodulin kinase Type II (CaMKII)mediated phosphorylation of Ser831GluA1 and enhanced estimated AMPAR singlechannel conductance. Similar mechanisms of glutamatergic plasticity have also been observed in the nucleus accumbens following prolonged psychostimulant use, which may be involved in mediating the addictive properties of these drugs. Thus, CaMKII-mediated enhancement of GluA1 receptors is a highly conserved, final common signaling mechanism for normal physiological processes such as memory formation, as well as the pathophysiological development of physical dependence to drugs of abuse.

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ROLE OF GLUTAMATE RECEPTOR REGULATION IN DRUG ABUSE Glutamate receptor regulation in the mesocorticolimbic system has been implicated in mediating a variety of drug-related behaviors during the use of and withdrawal from numerous of drugs of abuse. Modulation of glutamatergic systems within the mesolimbic reward pathway including the ventral tegmental area (VTA) and nucleus accumbens (nAc) were reported to be involved in drug-seeking and other addictive behaviors. The literature on the role of glutamatergic plasticity in drug-induced behaviors is quite broad dependent on drug of abuse studied, drug treatment or withdrawal paradigm used or behavior examined. The reader is referred to numerous excellent reviews on these topics [1-7]. Glutamate receptor regulation was also demonstrated in limbic areas such as the hippocampus and amygdala associated with drug context-induced relapse to drug-seeking and withdrawal behaviors, as well as drug salience and conditioned behaviors, respectively. A role for the glutamatergic system in mediating withdrawal symptoms was implied from the ability of glutamate antagonists to reduce the expression of withdrawal behaviors associated with the use of a range of self-administered drugs, including psychomotor stimulants such as amphetamine, nicotine and cocaine and central nervous system (CNS) depressants, such as opiates, ethanol and barbiturates. This review will present an overview of the physiological mechanisms underlying glutamatergic plasticity in the CA1 region of the hippocampus that regulate the expression of benzodiazepine withdrawal-anxiety. The methodological approaches, outcomes and interpretations from which these glutamatergic mechanisms were derived are further detailed in the publications cited. The mechanisms will be discussed in the context of the mechanisms underlying activity-dependent glutamatergic plasticity, as well as drug-induced plasticity to other drugs of abuse. GABA-A receptors are ligand-gated anion channels permeable to Clí and HCO3í, which open in response to presynaptic release of GABA, the main inhibitory neurotransmitter in the mammalian CNS [8]. Benzodiazepines enhance phasic inhibitory postsynaptic currents (IPSCs), in heteropentameric GABA-A receptors containing Ȗ a subunit, which are predominantly localized in the neuronal synapse [9]. At saturating concentrations of GABA in the synaptic cleft [10], benzodiazepines typically increase the frequency of single channel openings and prolong the decay of IPSCs by enhancing GABA affinity [11]. Neuronal inhibition mediated by GABA-A receptors balances excitatory postsynaptic currents (EPSCs) generated by cation (Na+, K+, Ca2+) flux through glutamate-activated excitatory amino acid receptors. EPSCs have a bi-exponential decay time-course: Į-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPARs) mediate the early fast decay component, while the late slow component is mediated by Ca2+ flux through N-methyl-Daspartate receptors (NMDARs). Both receptors are tetrameric complexes of homologous subunit proteins [12]. Hippocampal CA1 pyramidal neurons express high levels of heteromeric GluA (GluR) 1–3 subunits [13, 14], whereas NMDARs are composed of GluN2 (NR2) A-D subunits assembled with at least one GluN1 (NR1) subunit [15].

ROLE OF GLUTAMATE NEUROTRANSMISSION IN BENZODIAZEPINE WITHDRAWAL-ANXIETY Several labs had identified a role for excitatory receptors in mediating withdrawal signs primarily based on the effectiveness of glutamatergic, i.e. AMPAR and NMDAR antagonists to prevent these behaviors [16], yet the precise mechanisms underlying the effectiveness of

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these drugs was vague, centering on theories of “homeostatic mechanisms of excitation/inhibition”, enhanced “sensitization” to proconvulsants and the regulation of excitatory receptor numbers (see for example [17]). The descriptive nature of such changes in glutamatergic strength associated with drug withdrawal hindered progress in this field. The Guidotti lab [18] was among the first to detect increased AMPAR GluA1 subunit expression in hippocampus corresponding to anxiety-like behavior following 4-day withdrawal from chronic diazepam treatment. The fact that hippocampal glutamatergic plasticity correlates with anxiety is not unexpected, since reciprocal septo-hippocampal glutamatergic afferents regulate the expression of anxiety. Further, benzodiazepine injection into the hippocampus has anxiolytic actions [19, 20]. Our laboratory initially observed a functional enhancement of glutamatergic strength, i.e. an increase in the amplitude of AMPAR-mediated miniature (m)EPSCs in CA1 neurons, but not dentate granule cells (Figure 1) in hippocampal slices from benzodiazepine-withdrawn rats coupled with a localized increased in AMPAR antagonist binding sites measured autoradiographically in CA1 (and CA2) stratum pyramidale and the proximal dendritic area of stratum radiatum (SR) [21]. Based on these findings, we proposed that the observed

Figure 1. AMPAR-mediated mEPSCs in hippocampal neurons from rats sacrificed 2 days after 1-week oral flurazepam (FZP) treatment. (A) Representative traces of mEPSCs from individual CA1 neurons from control (top) and FZP-treated (bottom) rats recorded in the presence of 1 ȝM TTX, 10 ȝM glycine and 30 ȝM bicuculline methiodide. Neurons from FZP-treated rats showed an increased mean mEPSC amplitude when compared to neurons from control rats. Right: Representative average mEPSC from a control CA1 neuron (n = 83 events) and a neuron from an FZP-treated rat (n = 73 events) different from those shown in traces. Following 1-week FZP treatment, there was a 33% increase in average mEPSC amplitude in CA1 pyramidal neurons relative to control neurons. (B) Representative traces of mEPSCs recorded from individual dentate granule (DG) neurons from control (top) and FZP-treated (bottom) rats recorded in the presence of 1 ȝM TTX, 10 ȝM glycine and 50 ȝM picrotoxin. Right: Representative average mEPSC from a control dentate granule neuron (n = 165 events) and a neuron from an FZPtreated rat (n =193 events) different from those shown in traces. There was no difference in average mEPSC amplitude in dentate granule neurons from FZP-treated rats relative to control neurons. Reproduced with permission from Van Sickle BJ, Tietz EI. Neuropharmacology. 2002 Jul;43(1):11-27.

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hyperexcitability of CA1 neurons, a node in the anxiety circuit may provide a neurophysiological marker for expression of anxiety during drug withdrawal [22, 23]. We therefore began a systematic evaluation of the mechanisms of glutamatergic plasticity in the hippocampal CA1 region in relation to anxiety expression in our well-established benzodiazepine withdrawal model.

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CHRONIC BENZODIAZEPINE TREATMENT AND WITHDRAWAL Using this rodent model of withdrawal-anxiety, we uncovered the bi-directional regulation of AMPA and NMDA neurotransmission associated with anxiety in both juvenile rats and young adult rats following 1-week oral treatment with the water soluble benzodiazepine, flurazepam. Following 2-4 days adaptation to the animal facility and the 0.02% saccharin water vehicle, rats are offered ad lib access to flurazepam dihydrochloride (pH 5.8-6.2) for 1 week (100 mg/kg X 3 days; 150 mg/kg X 4 days) as their sole source of drinking water. Matched control rats receive saccharin water vehicle in parallel throughout all treatment and withdrawal phases. The brain concentration achieved immediately after ending treatment is ~1.2 PM flurazepam (equivalent to 0.6 PM diazepam) and is related to flurazepam’s relative oral bioavailability and half-life in rats (50% 2 days after drug removal, both in isolated CA1 neurons and in hippocampal slices (Figure 2) [41]. We next evaluated the temporal pattern of the regulation of AMPA- and NMDAmediated currents in our model in relation to anxiety-like behavior in the same rats. We found that AMPAR and NMDAR currents were reliably, bi-directionally regulated: AMPA currents were progressively increased after 1-day (15-30%) and 2 days (30-50%) in flurazepamwithdrawn rats, while NMDA currents were decreased (50%), but only after 2 days of withdrawal (Figure 3). Unexpectedly, anxiety in the elevated plus maze was only evident in 1-day, but not 2-day flurazepam-withdrawn rats [22].

Figure 2. NMDA-induced concentration-response. NMDAR-mediated currents were elicited in CA1 pyramidal neurons acutely dissociated from the hippocampus of rats sacrificed 2 days after withdrawal from 1-week oral flurazepam (FZP) treatment. Currents were recorded (VH = 30mV) in papaindissociated CA1 neurons in Mg2+-free buffer after U-tube application (10 s) of increasing concentrations of NMDA (1–3000 ȝM). There was no significant shift (p = 0.50) in the EC50 in individual control (n = 9 from 5 rats) and 1-week FZP-withdrawn (n = 8 from 5 rats) dissociated neurons. The maximal current elicited by NMDA application was significantly decreased (p = 0.04) in individual CA1 neurons from FZP-withdrawn rats in comparison to controls. The fit of the pooled data from dissociated neurons from control (EC50 = 37.1 ȝM; Imax -1170 ± 24.5 pA) and 1-week FZPwithdrawn rats (EC50 = 27.5 ȝM; Imax -373.4 ± 35.2 pA) is illustrated. Reproduced with permission from Van Sickle BJ, Cox AS, Schak K, Greenfield LJ Jr, Tietz EI. Neuropharmacology. 2002 Sep;43(4):595-606.

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Figure 3. Temporal pattern of glutamate receptor-mediated current regulation in CA1 pyramidal neurons and anxiety-like behavior during flurazepam (FZP) withdrawal. (A) Average AMPAR mEPSC amplitude (VH=-80 mV) in CA1 neurons from control (CON, black bars) or FZP-withdrawn rats (white bars) euthanized at 0, 1, 2, or 4 days of withdrawal from flurazepam. (B) Average NMDAR eEPSC amplitude (VH=-20 mV) in CA1 neurons from CON or FZP-withdrawn rats euthanized at 0, 1, 2, or 4 days of withdrawal from FZP. Anxiety-like behavior was measured in an elevated plus-maze. Rats were tested 1 day after an acute gavage of desalkyl-flurazepam (CON: n=7, d-FZP, n=8) or at 0 (CON: n=8; FZP, n=8), 1 (CON: n=9; FZP, n=8), 2 (CON: n=7; FZP, n=8) or 4 (CON: n=7; FZP, n=7) days of withdrawal from FZP (CON: black bars; FZP white bars). (C) Open-arm entries expressed as a percent of total entries. There was a significant reduction (33%) in open-arm entries in 1-day FZP-withdrawn rats relative to vehicle-treated control rats that was not evident after acute desalkyl-flurazepam treatment nor at 0, 2, or 4 days of flurazepam withdrawal. (D) Open-arm time expressed as a percent of total time. Using this measure, only 1-day FZP-withdrawn rats demonstrated increased anxiety-like behavior, measured as a significant reduction (70%) in the time spent on open arms. Data were analyzed by MANOVA with post hoc comparison of means by the method of Scheffe´. Asterisks denote significant differences between control and FZP withdrawn groups, p 100 nM decrease glutamate release following activation of a G protein and the modulation of adenylate cyclase (AC) and PKA activity. [KA] < 100 nM facilitates glutamate release following activation of AC and PKA.

Inhibition of Glutamate Release by Presynaptic KARs at Diverse Synapses Other than in the hippocampus, presynaptic KAR-mediated suppression of glutamate release occurs at thalamocortical synapses [54], globus pallidus [51], nucleus accumbens [55,56] and dorsal root ganglion neurons [57]. Presynaptic KARs in the globus pallidus certainly involve G-protein coupling and PKC activation, and can therefore be considered as

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metabotropic. The presynaptic KARs at thalamocortical synapse [54] display a common behaviour with the aforementioned hippocampal metabotropic presynaptic KARs at CA1 synapses in that their action is developmentally downregulated. However, it remains to be seen whether these and the other examples of inhibitory KARs affecting glutamate release have a metabotropic mode of action.

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POSTSYNAPTIC METABOTROPIC ACTIONS OF KARS The metabotropic actions of postsynaptic KARs and their importance in neuronal excitability have been increasingly realized in recent years. The slow afterhyperpolarization (sAHP) in neurons follows short bursts (lasting seconds) of action potentials and is generated by a voltage-independent Ca2+-dependent K+ current (IsAHP) [58], proportionally to the number and frequency of action potentials. In hippocampal CA1 pyramidal neurons, this sAHP is inhibited by KA [59], an effect recapitulated by synaptically released glutamate [60]. Pharmacologically, the effect is evidently mediated by the activation of KARs with metabotropic action, given that it is not contingent on any ionotropic or network activity, but rather sensitive to blockade by inhibitors of G-proteins (NEM and PTX) and the PKC (calphostin C). Intriguingly, in addition to PKC, the long-lasting metabotropic action of KARs in CA1 pyramidal neurons also involves PKA and mitogen-activated protein (MAP) kinases, with the MAP kinase stimulation occurring downstream of PKC activation at least [61]. Activation of MAP kinase and downstream signalling may well, through long-term phosphorylation-dependent changes, underpin the near irreversible effect of KAR activation on the sAHP in CA1 neurons. The KAR-mediated regulation of the sAHP represents a novel physiological function at glutamatergic synapses that operates to directly control the excitability of CA1 pyramidal cells as shown by the application of KA. This may underlie the prolonged increases in the excitability of pyramidal neurons mediated by KA and precipitate, in part, the epileptogenic activity of the agonist. Postsynaptic excitability is also modulated by KARs in mouse CA3 pyramidal neurons through a metabotropic action that decreases both the slow (IsAHP) and medium (ImAHP) AHP currents [62]. The KAR-mediated modulation of the IsAHP and ImAHP amplitude is PKCdependent and is absent in pyramidal neurons from GluR6-/-, but not in GluR5-/- transgenic mice. The upshot from this is that GluR6-containing KARs mediate the AHP modulation and thereby, control the firing frequency of CA3 neurones [63] to instigate a long-lasting change in intrinsic neuronal excitability and neuronal firing patterns, such as single-spike and spikeburst firing. Interestingly, in contrast to the effect of KAR activation on the IsAHP in CA1 pyramidal cells (where the IsAHP modulation by KA or endogenous glutamate is essentially irreversible), in CA3 pyramidal cells, the AHP modulation by KARs is reversible when elicited by endogenous glutamate, This suggests that KAR-mediated modulation of postsynaptic excitability may be occur by distinct metabotropic mechanisms at CA3 and CA1 synapses. A key general question arising from the evident dual mode of KAR function is whether ionotropic and metabotropic activities can coexist in the same neuron, and if so, how these may be coded at the level of the receptor. A recent report addressing this issue at hippocampal MF-CA3 synapses [63], shows that KAR activation by endogenous glutamate reversibly

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inhibited the slow Ca2+-activated K+-current (IsAHP) to effect an increase in neuronal excitability. This effect is metabotropic based on sensitivity to inhibitors of G-protein (NEM) and PKC (calphostin C) and, crucially, occurs concurrently with the ionotropic KARmediated EPSCs in the CA3 pyramidal neurons. This is surmised from the shrewd use of GluR6-/- and KA2-/- mice knockout mice. Thus while in GluR6-/- mice, both the inhibition of the IsAHP, and ionotropic synaptic transmission mediated by endogenously released glutamate from MFs are lost, in KA2-/- mice, only the inhibition of the IsAHP is ablated, with the KARmediated EPSC being preserved. These data indicate that heteromeric coassemblies of KA2 subunits with the GluR6 subunits underpin the inhibition of the IsAHP in CA3 pyramidal cells by low concentrations of KA, and definitively confirm that the ionotropic and metabotropic actions of KARs are separable and distinct modes of modulation [63]. The proposed model is therefore that KARs can operate simultaneously in two modes at MF-CA3 synapses: (1) through a direct ionotropic action of GluR6 and, (2) an through an indirect G-protein-coupled mechanism requiring the binding of glutamate to KA2. Other than hippocampal preparations, cultured dorsal root ganglion neurons (DRGNs) provide a simple system for studying KAR function given their expression of receptor consisting almost exclusively of GluR5 subunits. Exposure of DRGNs to KA increases [Ca2+]cytosolic, an effect that is sensitive to Gi/o-protein inhibition by PTX and persistent in the absence of extracellular Ca2+ [64]. From this, metabotropically active KARs are postulated to effect Ca2+ mobilization from intracellular stores. KAR receptor action also causes a longlasting decrease in voltage-dependent Ca2+ channel activity which is sensitive to inhibition of Gi/o-protein (PTX) and PKC (bisindolylmalemide). The metabotropic actions of KARs are independent of ionotropic KAR activity, are abrogated in GluR5 deficient mice. Interestingly, spinal cord slice recordings of dorsal horn neurons indicate that the metabotropic KAR activity in DRGNs decreases in glutamate release from DRGN terminals. The question remains as to how metabotropically active KARs couple to the G-protein mediated signalling cascade they evidently stimulate. In general, there has been a dearth of information about how KARs interact with G-proteins to produce their metabotropic effect. Early reports of PTX –dependent agonist binding and agonist-dependent ADP-ribosylation of a 40kDa protein, pointed to a goldfish KA-binding protein interacting with a G-protein, and heterologously expressed frog KARs interacted with G-proteins [65-66]. More recently, the fact that KA2 subunits prove essential for the metabotropic action of KARs in suppressing the IsAHP in CA3 pyramidal cells provides a handle on learning how KARs couple to their downstream metabotropic effects. In biochemical analyses using an anti-GluR6 antibody, GluR6 and KA2 subunits are predictably co-immunoprecipitated given their putative GluR6/KA2 heteroassembly. More significantly, the immunoprecipitates also pull down GĮq-protein. In contrast, GluR6 immunoprecipitates from KA2-/- mice lack GĮq, suggesting that the KA2 subunit expedites direct or indirect interaction with GĮq. Thus, the mandatory requirement for the KA2 subunits for metabotropic modulation of the IsAHP may be contingent on the ability of the subunit to interact with GĮq/11-protein [63]. The role of GĮq/11 in IsAHP modulation is recognized from its activation by de facto GPCRs, e.g. muscarinic M(3)-cholinergic receptors and metabotropic (mGluR(5)) receptors [67]. Interestingly however, KAR-mediated inhibition of the IsAHP in CA1 pyramical cells is PTX-sensitive, suggesting coupling to a Gi/o-protein. Given the different identity of the G-proteins underpinning the IsAHP modulation CA3 and CA1 pyramidal neurons, it remains to be seen whether or not KAR subunits also interacts with the

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Gi/o-protein to mediate the metabotropic activity of KARs in the latter neurons. Detailed analysis of the GĮq/11 interaction with KA2 subunit interaction may provide key insights and it will be interesting to see if the KA1 subunit shares the ability of KA2 to interact with Gproteins to bridge GluR5/6/7 subunits to metabotropic signalling.

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CONCLUSION Having delineated a metabotropic modus operandi for KARs, a key question for future studies is the physiological significance of the “slow” transmission/modulation at the incumbent synapse. Another issue is, why the co-existence of KAR displaying ionotropic and metabotropic functions postsynaptically? Is it possible that the slow kinetics of native ionotropic KARs reflect co-activation of metabotropic processes that modify the ionotropic output? It is interesting in this regard that KARs depressing the sAHP through a metabotropic action in CA1 and CA3 neurons shape the postsynaptic output to control excitability of the target neuron in the first instance and then networks as a whole. It will be interesting to see how this excitability is developmentally regulated by the alteration of KAR behaviour. Increasingly, KAR have been shown to be involved in synaptic plasticity (LTP and LTD). This poses the question as to the relative contribution of ionotropic and metabotropic KAR activity in learning and memory and cognition processes. Finally, elucidating the involvement of KARs with metabotropic action in pathophysiological conditions in the CNS, remains a fundamental mission. The quest for KAR antagonists commercially may, not only aid the identification of agents active against, for example, epilepsy, but also better facilitate the delineation of ionotropic or metabotropic functions of KARs. Certainly, addressing the aforementioned questions warrants the concerted use of pharmacological tools and KAR subunit transgenic mice. Although, on the one hand the latter models may confound interpretation due to compensatory mechanisms [68], on the other hand, the elucidation of the precise KAR oligomer underpinning sAHP control using GluR6-/- and KA2-/- transgenics [63], is cause for encouragement for future studies. With respect to the molecular mechanisms underlying the metabotropic actions of KAR the burning issue is, how might KARs interact with a G protein and is this interaction direct or indirect? The observation that KA2 subunit interact with GDq will do much to further fuel the hunt for potential interacting partners (reviewed in ref. [69-70]. Could one of these partners provide the “bridge” for coupling of KARs to G-proteins, in addition to prevalent role of many of these proteins in the trafficking, insertion and internalization of KARs at synapse?. Where KAR-mediated modulation is shown to be dependent on G-protein, but independent of second messenger production, the question pertains to how the “membrane delimited” mechanism operates? Does it bear resemblance to the GȕȖ-mediate modulation of Ca2+ and/or K+ operated by several classical inhibitory GPCRs? In cases where KAR activation does lead to second messenger generation and activation of the cognate protein kinases (PKC and PKA), the targets for phosphorylation require elucidation. Although Ca2+ channels may present a target for PKC in the spinal cord, targets of the multifarious stimulation of PKC by KARs and MF KAR stimulation of PKA require investigation. Finally, G-protein independent activation of metabotropic signalling (AC/cAMP/PKA) is also

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observed in response to KA. The question remains, is this an indirect consequence of upstream activation of the ionotropic acitivity of KARs, or is this yet another facet of a “direct” metabotropic influence of KARs? The establishment of the presence of metabotropic activities for KARs has thrown up numerous questions. These will no doubt encourage extensive experimentation for many years to come and certainly provoke continued debate on the duality of KAR operation.

ACKNOWLEDGMENTS Part of the work performed by authors included in this review was supported by a Grant to AR-M from Spanish Ministry of Education and Science. BFU2006-14155.

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depression at the hippocampal mossy fiber-CA3 synapse. J. Neural. Transm., 114,1425-1431.. Kidd, F. L. et al. (2002) A presynaptic kainate is involved in regulating the dynamic properties of thalamocortical synapses during development. Neuron, 34, 635-646 . Crowder, T. L. and Weiner J. L. (2002) Functional characterization of kainate receptors in the rat nucleus accumbens core region. J. Neurophysiol., 88, 41-48. Casassus, G. and Mulle, C. (2002) Functional characterization of kainate receptors in the mouse nucleus accumbens. Neuropharmacology, 42, 603-611.. Kerchner, G. A. et al. (2001) Presynaptic kainate receptors regulate spinal sensory transmission. J. Neurosci., 21, 59-66. Lancaster, B. and Adams, P. R. (1986) Calcium-dependent currents generating the afterhyperpolarization of hippocampal neurons. J. Neurophysiol., 55, 1268-1282. Melyan, Z. et al. (2002). Metabotropic-mediated kainate receptor regulation of IsAHP and excitability in pyramidal cells. Neuron, 28:34(1), 107-14. Melyan, Z. et al. (2004). Metabotropic regulation of intrinsic excitability by synaptic activation of kainate receptors. J. Neurosci., 12:24(19), 4530-4. Grabauskas, G. et al. (2007) Protein kinase signalling requirements for metabotropic actions of kainate receptors. J. Physiol., 579(2), 363-373. Fisahn, A. et al. (2005) The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurones. J. Physiol., 1:562, 199-203. Ruiz, A. et al. (2005) Distinct subunits in heteromeric kainate receptors mediate ionotropic and metabotropic function at hippocampal mossy fiber synapses. J. Neurosci., 25(50), 11710-11718. Rozas, J. L. et al. (2003) Noncanonical signaling by ionotropic kainate receptors. Neuron, 31, 39, 543-53. Willard, J. M. et al. (1991) The interaction of a kainate receptor from goldfish brain with a pertussis toxin-sensitive GTP-binding protein. J. Biol. Chem., 266(16), 10196-10200. Ziegra, C. J. et al. (1992) Coupling of a purified golfish brain kainate receptor with a pertusis toxin-sensitive G protein. Proc. Natl. Acad. Sci. USA, 1, 4134-4138. Krause, M. et al. (2002) Functional specificity of GĮq and GĮ11 in the cholinergic and glutamatergic modulation of potassium currents and excitability in hippocampal neurons. J. Neurosci., 22, 666-673. Christensen, J. K. et al. (2004) A mosaic of functional kainate receptors at hippocampal interneurons. J. Neurosci., 24, 8986-8993. Isaac, J. T. R. et al. (2004) Kainate receptor trafficking: physiological roles and molecular mechanisms. Pharmacol. Ther. 104, 163-172. Jaskolski, F. et al. (2005). Subcellular localization and trafficking of kainate receptors. Trends Pharmacol. Sci., 26, 20-26.

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INDEX

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A abuse, ix, 105, 106, 118, 119, 124 access, 12, 44, 108 accounting, 2, 4 acetaminophen, 154, 158 acetic acid, 133 acetylcholine, 71, 78, 91, 101 action potential, 40, 70, 181, 186 activation, x, 125, 127, 128, 129, 131, 132, 134, 141, 142, 145, 146, 147, 150, 151, 156, 160, 164, 169, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187 active transport, 21, 128 adaptation, 73, 108, 113, 124, 167 adaptive immunity, 99 adenocarcinoma, 94 adenosine, 132, 170 adenylyl cyclase, 128, 130, 132, 178, 186 adhesion, 92, 93, 94, 95, 96, 98, 101, 102, 127, 130 administration, 130, 133, 136, 137, 139, 141, 142, 145, 146, 147, 148, 149, 150, 151, 152, 153, 160, 167 adrenal gland, 88, 100 adrenaline, 13, 14 adverse effects, 38 affective disorder, 62 age, 8, 16, 23, 30 agonist, 14, 37, 42, 43, 44, 45, 49, 50, 51, 94, 112, 114, 123, 132, 135, 142, 145, 146, 148, 151, 161, 166, 171, 174, 177, 178, 179, 180, 181, 182 aid, 183 alanine, 9, 13, 14, 19, 26, 29, 43, 45, 49, 63 albumin, 26 alcoholic liver disease, 8, 27 allodynia, 146, 147, 157 allosteric, 131 alpha, 126, 139, 140, 144, 154, 159, 162, 169 alternative, 155, 161, 165, 175

alters, 122 amide, 158 amplitude, 54, 107, 108, 110, 111, 113, 116, 117, 118, 172, 173, 174, 175, 176, 177, 178, 181 amygdala, 106, 120, 126, 127, 129, 132, 134, 135, 136, 137, 139, 140, 156, 158, 159, 160, 161, 162, 163, 165, 166 amyotrophic lateral sclerosis, vii, 1, 4, 24, 27, 69, 81, 88 analgesia, 126, 150, 156, 157, 165, 166 analgesic, x, 125, 149, 152, 153, 158, 167 analgesic agent, x, 125 analgesics, x, 125, 126, 149, 150, 155 anoxia, 71 antagonism, 39, 61, 152, 176 anterior cingulate cortex, 146, 147, 160, 166 antibody, 93, 182 anticoagulation, 18 anti-inflammatory drugs, 149, 154 antinociception, 130, 142, 145, 149, 151, 153, 155, 158, 159, 160, 161, 163, 165, 166, 167, 168 antioxidant, 10, 28, 95 antipsychotic, viii, 35, 49, 53, 56, 59, 62 antipsychotic drugs, viii, 35, 56, 59, 62 antisense, 149 antisense oligonucleotides, 149 anxiety, ix, 105, 106, 107, 108, 109, 110, 111, 113, 118, 120, 122, 130 apoptosis, vii, 1, 3, 21, 71, 77, 94, 104 application, 136, 149, 171, 173, 181 arachidonic acid, 151, 158 arginine, 37, 165 argument, 173, 179 arousal, 120 arrest, 94 artery, 7, 21, 25, 26, 28, 32, 34 arthritis, 89, 137, 148 aspartate, viii, 9, 14, 19, 25, 27, 35, 36, 37, 39, 42, 43, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 76, 78, 79, 80, 98, 99, 100, 101, 102, 106,

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Index

119, 120, 121, 126, 131, 143, 155, 157, 158, 163, 164, 165, 167, 170, 184 aspartic acid, 161 asphyxia, 21, 33 assessment, 148 asthma, 89 astrocytes, ix, 3, 37, 62, 67, 71, 74, 75, 76, 79, 80, 81, 82, 83, 87, 88, 92, 98, 101, 102 astrocytoma, 94 asymptomatic, 71 atherosclerosis, 89 athletes, 19, 33, 71 autism, 69 autoimmunity, 88 aversion, 160 avoidance, 146, 160 avoidance behavior, 160

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B barbiturates, 106 basal ganglia, 39, 52 base, 61, 164 basket cells, 129 beneficial effect, 2, 5, 12, 38 benzodiazepine, ix, 105, 106, 107, 108, 110, 111, 113, 118, 119, 120, 121, 122, 123, 157, 159, 165, 170 bile, 79 binding, 127, 129, 130, 131, 149, 157, 165, 182, 187 bioavailability, 108 bleeding, 18 blockades, 29 bradykinin, 92, 126 breakdown, 11, 13, 15, 19 broad spectrum, 177 burning, 183

C calcitonin, 93, 94 calmodulin, 179 calyx, 184 cannabinoids, 149, 152, 163 cannabis, 44 capillary, vii, 1, 3, 5, 23, 94 carbohydrate, 72 carcinoma, 94, 104 cartilage, 88, 89 cascades, x, 40, 46, 169, 171, 177 casein, 74, 77 catecholamines, 14, 29

catheter, 6, 7 cation, 37, 40, 42, 46, 72, 106, 108 chemiluminescence, 28 chemotaxis, 93, 100 children, 23 chloral, 20 chloride, 128, 129 cholecystokinin, 163 choline, 72 cholinergic, 182, 187 chorea, 56, 88 choroid, 23 chronic obstructive pulmonary disease, 33 chronic pain, 133, 136 chronic renal failure, 7 cingulated, 140 circulation, 6, 13, 19, 21, 89, 94 citalopram, 27 clarity, 170 classes, 59, 88, 127, 152 classical, 178, 179, 183 classification, 154, 171 cleavage, 37, 103 cloning, 130 clozapine, 57 cocaine, 106, 119, 120, 124 coefficient of variation, 170 co-existence, 183 coffee, 16 collagen, 21 collateral, 113, 170, 174 colleges, 6, 8, 14, 17 colon, 94 coma, viii, 67, 72 communication, 2, 55, 88, 127 compartment syndrome, 19 complement, 113, 130, 154, 158 complexity, 171 complications, 4 components, 127, 158 composition, 46, 57, 104, 121, 123, 132, 165 compounds, 9, 38, 42, 43, 44, 72, 75, 129, 131, 133, 135, 138, 139, 140, 145, 147, 150, 151, 153 compression, 28 concentration, 128, 132, 142, 166, 178, 180 conductance, ix, 43, 44, 81, 105, 115, 116, 117, 118, 121, 123, 129, 130, 131, 155 configuration, 129 conflict, 39 congestive heart failure, 71 conjugation, 158 connectivity, 2, 90, 136 conscious awareness, 55

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Index consensus, 113, 130, 131, 160 constraints, 153 construction, 90 consumption, 16 contradiction, 7, 16 controversial, 15 contusion, 28, 31 convergence, 54 cooling, 18 cooperation, 61 coordination, 40 corpus callosum, 92 correlation, vii, 1, 6, 7, 8, 9, 10, 12, 16, 38, 56, 111 correlations, 51 cortex, 33, 39, 48, 76, 82, 91, 121, 126, 137, 140, 141, 142, 146, 147, 152, 158, 159, 160, 162, 163, 166, 168, 184 cortical neurons, 32, 41, 62, 73, 80, 90, 91, 121, 158, 164, 184 cortisol, 13 cost, 126 coupling, 180, 182, 183 cranial nerve, 92 craniotomy, 14 crepitus, 8, 16, 27 crystal structure, 54 cues, 89 culture, 51, 75, 76, 101 cyclic AMP, 186 cycling, 83 cysteine, 37, 41, 69 cystine, 28, 95, 104 cytoskeleton, 77, 93 cytosolic, 128, 179, 182

D damages, viii, 67 decay, 106, 113 declarative memory, 47 defects, 92 defence, 121 deficiency, 16, 20, 31, 38, 44 deficit, 24, 46, 48, 60, 116, 161 degradation, 41, 50 degradation process, 41 dehydration, 84 dehydrogenase, 128 delivery, 153 dementia, 4, 6, 7, 8, 24, 25, 31 dendrites, 127, 130, 133, 176, 177 dendritic cell, 88, 103 density, 127

191

depersonalization, 47 dephosphorylation, 43 depolarization, 36, 42, 43, 70, 79, 84, 109, 128, 179, 186 depressants, 7, 106, 156 depression, 7, 26, 40, 159, 170, 171, 172, 173, 174, 177, 179, 186, 187 deprivation, 32 desensitization, 45, 59, 61, 112, 113, 158 detachment, 96 detectable, 11 developing brain, 22, 24, 90, 92, 121 developmental change, 108, 167 diabetes, 30 diacylglycerol, 176 dialysis, 17, 31, 32 diet, 29 diffusion, 3, 20, 71, 84 directionality, 175 diseases, 28, 41, 51, 52, 69, 88, 89 disinhibition, 156, 158, 162, 185 disorder, 8, 36, 38, 49, 51, 58, 71, 72 displacement, 71 distribution, 5, 11, 19, 21, 23, 41, 44, 45, 49, 56, 71, 88, 114, 123, 127, 130, 157, 167 divergence, 74, 173 diversity, 53, 120, 148, 155, 162, 163, 167 dopaminergic, 36, 39, 42, 60 dorsal horn, 126, 155, 157, 164, 182 dosage, 12 dosing, 47 drinking water, 108 duality, 184

E edema, 10, 17, 31, 32, 34, 72, 80 electrodes, 174 electrolyte, 5, 71 electron, 74, 111, 121, 159 electron microscopy, 111 electrophysiological properties, 129, 154 elucidation, 129, 145, 149, 175, 183 embryogenesis, 89, 91, 101 embryonic stem cells, 89 emergency, 71 encephalopathy, 7, 26 encoding, 121, 163, 165 encouragement, 183 end stage renal disease, 17 endothelial cells, 3, 89, 99 endothelium, 3 endurance, 33

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192

Index

energy, 10, 36, 75, 77, 156 enlargement, 74 environment, 78, 95, 104, 124 enzyme, 11, 12, 16, 29, 48, 50, 64, 128 enzymes, viii, 2, 9, 12, 16, 18, 20, 41, 48, 128, 150, 151 epidemiology, 78 epilepsy, 27, 84, 85, 88, 171, 183 epileptogenesis, 102 epithelial cells, 82 erythrocytes, 26 esophageal cancer, 95 esophagus, 88 ester, 28, 144 ethanol, 106, 109, 121, 124 etiology, 47 evidence, viii, x, 2, 6, 15, 16, 26, 31, 35, 36, 38, 50, 52, 53, 54, 60, 70, 73, 76, 80, 81, 88, 91, 98, 100, 120, 121, 125, 127, 130, 135, 136, 139, 141, 147, 149, 153, 155, 157, 162, 167, 169, 171, 173 excitability, 37, 41, 43, 71, 84, 122, 133, 171, 175, 181, 182, 183, 187 excitation, 39, 51, 107, 121, 132, 163 excitatory postsynaptic potentials, 40, 126, 131 excitatory synapses, 36, 49, 51, 52, 111, 115, 123 excitotoxic, 171, 175 excitotoxicity, 3, 41, 45, 51, 53, 80, 85 excretion, 79 exercise, 19, 33 exocytosis, ix, 55, 67, 70, 73, 74, 75, 76, 77, 78, 79, 84, 85, 184 exploitation, 129 extinction, 57 extracellular matrix, 92, 94, 95, 96, 101 extracts, 100 extrusion, 73

F families, 68, 129, 171 family, 131, 132, 155, 167 fatty acid, 158 fear, 159, 163 female rat, 30 fetal development, 44 fetal growth, 33 fetus, 21 fever, 32 fluctuations, ix, 13, 67, 101 fluid, vii, 1, 2, 11, 68, 72, 73, 93, 117 fluorescence, 156 fluoxetine, 27 fluvoxamine, 27

focusing, 137 follicle, 31 follicle stimulating hormone, 31 foramen, 71 force, 69 forebrain, 30, 32, 44, 63, 91, 147, 167, 168 formation, 2, 18, 37, 56, 69, 70, 92, 94, 98, 150, 151 frog, 182 frontal cortex, 54 fuel, 183 functional changes, 108 functional imaging, 153 functional MRI, 6 fusion, 70, 74, 77

G gadolinium, 85 ganglion, 180, 182 gastrointestinal tract, ix, 87 gastrulation, 89 gene, 130, 157, 165, 166, 167 gene expression, 48, 50, 54, 93, 165 generation, 136, 183 genes, 54, 58, 64, 98, 131, 133 genetic disease, 102 genetics, 102 gestation, 33 gestational diabetes, 33 glaucoma, 4, 24 glia, 23, 55, 62, 73, 90, 91 glial, 128, 160 glial cells, 48, 49, 68, 69, 75, 76, 78, 80, 82, 88, 89, 90, 92, 97, 98, 128 glioblastoma, 96, 104 glioma, 4, 75, 95, 96, 101, 104 globus, 171, 179, 180, 186 glucagon, viii, 2, 6, 14, 15, 25, 30, 99 gluconeogenesis, 25 glucose, viii, 2, 14, 15, 30, 32, 100 glucose tolerance, 30 glue, 53 glutathione, 95 glycine, viii, 21, 24, 27, 35, 37, 42, 43, 44, 45, 48, 49, 50, 51, 52, 53, 56, 57, 58, 59, 60, 61, 62, 63, 70, 73, 75, 107, 131, 144, 154, 157, 165 gout, 9, 28 granules, 69 gray matter, 126, 161, 165 groups, 133 growth, 7, 15, 16, 20, 24, 31, 77, 91, 94, 95, 98, 103, 104

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Index

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H hair, 145 half-life, 108 head injury, 14, 18, 24, 25, 26, 29, 71 head trauma, 34 headache, 8, 27, 72 healing, 93, 103 health, 61, 81, 126 hemisphere, 76 hemodialysis, 17, 26, 32 hemodynamic instability, 18 hepatic encephalopathy, 17, 31 hepatic failure, 14 hepatitis, 13 hepatocytes, 74, 83 Hermes, 167 hexane, 143 hippocampal, 159, 162, 163, 165, 171, 172, 174, 175, 177, 178, 181, 182, 184, 185, 186, 187 histamine, 126 histidine, 27 histological examination, 10 homeostasis, viii, 2, 14, 72, 79, 82 hormone, 13, 33, 50, 77, 88, 91, 101, 157 hormones, viii, 2, 17, 20, 68, 130 host, 96 hot water, 134 hydrocortisone, 20, 33 hydrolysis, 132 hydroxyl, 10, 37, 123 hyperactivity, 39 hyperalgesia, 140, 147, 149, 156, 157, 158, 161, 162, 164, 166, 167 hyperglycemia, 15 hyperinsulinemia, 15 hyperkalemia, 18 hypernatremia, ix, 67, 81 hypertension, 32 hyperthermia, 19, 20, 33 hyperthyroidism, 20 hyperuricemia, 28 hyponatremia, viii, 67, 71, 72, 73, 79, 81, 83, 84, 85 hypothalamic, 160, 185 hypothalamus, 91, 126, 137, 153 hypothermia, 18, 32 hypothesis, x, 13, 16, 38, 39, 48, 50, 53, 54, 55, 59, 111, 169, 174, 176 hypothyroidism, 20 hypoxia, 4

193

I ideal, 21 identification, 50, 54, 148, 183 identity, 40, 182 ileum, 98 illusions, 47 image, 72 images, 74, 115 imaging, 153 immersion, 134 immobilization, 19, 20 immune function, 89 immune system, 93 immunodeficiency, 28 immunofluorescence, 113 immunohistochemistry, 150 immunomodulatory, 88 immunoreactivity, 167 impairments, 36 impulses, 127 inactivation, 161, 179 incidence, 15, 18 independent living, 36 India, 87 indirect effect, 173 individuals, 38, 47 indole, 144 induction, 7, 32, 40, 58, 96, 113, 116, 161, 176, 178 ineffectiveness, 175 infarction, 13, 34 infection, 93 ingestion, 30, 33 inhibition, 10, 23, 32, 38, 39, 47, 50, 54, 57, 61, 63, 74, 75, 76, 77, 93, 95, 96, 106, 107, 120, 130, 147, 150, 151, 152, 154, 155, 156, 158, 162, 163, 164, 166, 167, 168, 173, 175, 176, 179, 182, 184, 185, 186 initiation, 7, 9, 18, 22, 186 injection, 135, 136, 137, 138, 139, 140, 141, 145, 150, 151, 160, 161 injections, 58 injuries, 19, 24, 32 injury mechanisms, 57 inositol, 75, 80, 81, 82 insertion, ix, 14, 58, 82, 105, 116, 119, 183 insulin, viii, 2, 6, 7, 14, 15, 23, 24, 29, 30, 88, 100 integrin, 85, 92, 93, 96, 101, 102 integrins, 77, 79, 84 integrity, 4, 5, 37, 45 interaction, 131, 152, 166, 182, 183, 187 interactions, 130, 164 interference, 4

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194

Index

internalization, 43, 183 interneuron, 39, 129, 136, 156, 164, 172, 173, 174, 175, 176, 179 interneurons, 44, 52, 90, 92, 102, 129, 132, 154, 157, 160, 164, 171, 173, 174, 175, 178, 179, 185, 186, 187 intervention, 79, 97, 149 intestine, 88 intracellular calcium, 71, 93 intracerebral, 139, 148 intracerebral hemorrhage, 4, 24 intracranial pressure, 18 intravenously, 9, 12, 47 intrinsic, 157, 160, 181, 187 ion channels, 37, 40, 41, 42, 53, 70, 97, 101, 120, 128, 131 ionotropic glutamate receptor, x, 131, 147, 155, 169, 170, 171 ions, 68, 70, 77, 78, 129, 130, 131 Ireland, 125, 153 irritability, 72 ischemia, 4, 18, 28, 29, 30, 32, 34, 69, 74, 75, 76, 80, 82 isoforms, 129, 130, 131, 165, 166

J

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jaw-opening reflex, 145 joints, 126

K kainate receptor, 128, 131, 132, 142, 147, 155, 159, 160, 167, 170, 174, 184, 185, 186, 187 kappa, 162, 164 keratinocyte, 88 keratinocytes, 97, 99 kidney, 32, 74, 88 knockout, 129, 130, 148, 163, 182

L labeling, 114, 115, 116 landscape, 57 laparotomy, 14 large-scale, 174 latency, 134, 135, 139, 140, 141, 142, 145, 151, 152 lateral sclerosis, 8 lead, vii, 1, 2, 9, 12, 17, 18, 22, 36, 40, 71, 77, 78, 88, 119, 128, 146, 183

learning, ix, 2, 36, 40, 42, 48, 59, 68, 81, 87, 132, 171, 182, 183, 186 lens, 28 lethargy, 72 leukocytes, 89 lice, 182 ligand, 40, 41, 42, 54, 60, 93, 106, 127, 148, 156, 171 ligands, 127, 148, 149, 157 light, 91, 159 limbic system, 120 linkage, 127 lipases, 41 lipoxygenase, 126, 151 liquid chromatography, 121 local anesthesia, 18 localization, 37, 45, 64, 100, 130, 157, 159, 174, 187 loci, 126, 141 locus, 64, 179 longevity, 178 long-term potentiation, 160, 171, 186 luteinizing hormone, 101 lysergic acid diethylamide, 52

M machinery, 74 magnesium, 33, 42, 51 magnetic resonance, 5, 85 magnetic resonance imaging, 5 magnetic resonance spectroscopy, 85 magnitude, 48 major depression, 7, 27 majority, 17, 71, 75, 90, 92, 113, 127, 129, 137, 138, 153 malignancy, 96 malignant tumors, 94 mammalian brain, 36, 39, 53, 98, 127 mammals, 97 man, 29, 33, 68 management, 47, 81 manipulation, 127, 152 mapping, 161 mass, 7, 89 matrix, 94 matter, iv, 54, 78, 126, 161, 165 maturation, 175, 185 media, 95 mediation, vii, x, 101, 125, 127, 134, 136, 141, 146, 153, 156, 186 medical, viii, 35 medication, 44, 60

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Index medulla, 99, 126, 127, 134, 135, 139, 140, 156, 158, 159, 162, 165, 166, 167 medulloblastoma, 94, 95 melanoma, 94, 95, 103 melatonin, 100 membranes, 18, 69, 70, 149 memory processes, 171 meningitis, vii, 1, 4 menopause, 30, 31 menstrual cycles, 31 mental fatigue, 33 mental retardation, 69, 89 messenger RNA, 61 messengers, 37, 40, 51, 79, 128, 161 meta-analysis, 56, 63 metabolic, 127 metabolic pathways, 69 mice, 15, 25, 52, 56, 57, 60, 91, 95, 96, 101, 113, 118, 129, 130, 132, 133, 147, 148, 149, 152, 157, 159, 161, 163, 165, 168, 181, 182, 183, 186 microdialysis, 5, 14, 23, 28, 64, 136, 137, 151, 164, 165 microinjection, 134, 135, 141, 142, 145, 146, 147, 148, 149, 150, 151, 152, 158 micrometer, 116 microorganisms, 93 midbrain, 44, 124, 126, 162, 164 migraines, 8 migration, 56, 89, 90, 91, 92, 93, 94, 96, 97, 100, 101, 102, 103, 104 military, 71 mineralization, 88 miniature, 107, 173, 176 mirror, 147 mission, 183 mitochondrial, 128 mitogen, 43, 88, 98, 170, 181, 184 mitogen-activated protein kinase, 170, 184 modality, 145 models, vii, viii, x, 1, 2, 4, 12, 28, 36, 45, 47, 50, 55, 60, 115, 118, 119, 120, 125, 130, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 146, 147, 148, 150, 153, 171, 183 modifications, 161 modulation, x, 125, 126, 127, 133, 134, 136, 139, 141, 147, 150, 151, 152, 153, 155, 157, 158, 159, 160, 163, 164, 167, 168, 171, 173, 175, 177, 179, 180, 181, 182, 183, 184, 185, 187 modules, 130, 154, 158 modus operandi, 61, 183 monkeys, 163 monoamine, 153 monoaminergic, 152

195

monosodium glutamate, 19, 29 morbidity, 36 morphine, 150, 151, 153, 154, 155, 156, 159, 160, 161, 162, 163, 165, 166 morphological, 163 morphometric, 74 mortality, 4, 10, 34, 72 mortality rate, 4, 10, 72 mosaic, 187 motivation, 68 motor neuron disease, 8, 27 mouse, 135, 137, 139, 140, 141, 142, 145, 146, 148, 149, 151, 152, 159, 161, 166, 168, 181, 186, 187 multiple sclerosis, 88, 89 muscle, 126 muscular mass, 21 mutant, 159 mutation, 49, 118 mutations, 129, 186 myelin, 92, 102 myocardial infarction, 13, 29 myoglobin, 19, 20

N naloxone, 150, 151, 166 natural, 127 nausea, 71 necrosis, 3, 21 negative effects, 22 neocortex, 45, 60, 154 neonatal, 159, 174, 176, 178, 179, 185 neonate, 176, 179 nerve, 37, 68, 69, 70, 73, 74, 76, 77, 79, 80, 81, 85, 93, 128, 133, 135, 136, 139, 140, 145, 146, 148, 163, 172, 174, 178, 184 nervous system, ix, 2, 43, 52, 68, 71, 87, 88, 89, 92, 93, 106, 127, 129, 132, 158, 159 network, 126, 160, 175, 176, 179, 181, 186 neuropathologies, 24 neuropeptide, 153 neuropeptides, 42, 93 neuroprotection, vii, 2, 4, 10, 11, 12, 13, 16, 17, 18, 21, 22, 25, 26, 30, 32, 34, 41 neuroprotective agents, 16 neuropsychopharmacology, 55 neurotoxicity, 3, 4, 9, 21, 41, 42, 48, 52, 54, 59, 88 neutral, 12, 134, 150 neutrophils, 88, 93, 97 nicotine, 106 nigrostriatal, 60 nitric oxide, 41, 100, 156, 161 nitrogen, 23, 36

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Index

non-steroidal anti-inflammatory drugs, 149, 154 norepinephrine, 61, 74, 84, 89 normal, 136, 156, 163, 173, 175 nuclei, 90, 126, 134, 135, 137, 139, 140, 146, 148, 168 nucleus, ix, 53, 105, 106, 124, 126, 134, 135, 137, 139, 140, 141, 145, 150, 154, 159, 165, 167, 180, 187 nucleus accumbens, 165, 180, 187 nucleus tractus solitarius, 53 nystagmus, 47

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O observations, 173, 175 occlusion, 7, 26, 28, 34 oculomotor, 47, 61 oedema, 79 olanzapine, 55 oligodendrocytes, 88 oligomer, 183 oligonucleotides, 149 oophorectomy, 31 opiates, 20, 106 opioidergic, 150 opioids, 149, 151, 155, 162, 166, 167, 168 organ, 78, 145 organism, 89 organs, 5, 93, 126 ornithine, 103 oscillation, 91, 92 osmolality, 83 osmotic stress, 74, 75, 76, 81, 82 osteoporosis, 88 overlap, 127 ovulation, 16 oxide, 156, 161 oxygen, 18, 32 oxytocin, 154

P pancreas, ix, 4, 15, 24, 30, 87, 88 pancreatic cancer, 94, 103, 104 paradoxical, 146 parallel, 45, 108, 113 parameter estimation, 62 parenchyma, 5, 10, 71 participants, 19 parvalbumin, 52, 129, 163 passive, 173 pathogenesis, 7, 9, 28, 39, 64, 81

pathology, 21 peptide, 85, 93, 94, 116, 117, 130, 157 peptides, 23 perception, x, 125, 126, 156 perfusion, 5, 25, 30 periaqueductal gray matter, 126, 165 permeability, 10, 23, 42, 44, 59, 104, 122, 131, 132, 156, 157, 161 permeant, 179 permeation, 96 permit, 45 peroxide, 10 personality, 58, 59 pertussis, 170, 171, 172, 176, 177, 178, 180, 187 pharmacokinetics, 147 pharmacotherapy, 53, 55 phencyclidine, 38, 43, 51, 52, 55, 60 phenotype, 63, 88, 93 phenotypes, 50, 57 phosphate, 144 phosphinic acid, 139, 144 phospholipase C, 128, 132, 161, 170, 171, 176 phospholipids, 132 phosphorylates, 176 phosphorylation, ix, 43, 91, 105, 115, 118, 119, 121, 123, 181, 183 physical activity, 16 physical exercise, 19 physical interaction, 171 physiological, 132, 133, 148, 175, 181, 183, 187 Physiological, 56, 61, 89, 98, 102, 103, 163 physiological mechanisms, 106 physiology, vii, viii, 30, 35, 50, 78, 108, 113, 170, 184 pineal gland, ix, 87, 88 pituitary gland, 100 placebo, 56, 57 placenta, 21, 22 plantar, 137 plants, ix, 87 platelets, ix, 8, 21, 87, 100 play, x, 125, 145, 150, 171, 175 playing, viii, 9, 35, 153 plexus, 23, 98 point mutation, 129 polarization, 93 polydipsia, 71 polymerase, 10, 100 polymerization, 93 polysialic acid, 92, 102 pools, 30, 71, 78 population, 16, 23, 30, 47, 50, 58, 118, 126, 185 pore, 131

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Index positive correlation, 9, 22, 111 positive feedback, 15 postsynaptic, 126, 127, 128, 129, 131, 132, 142, 145, 155, 165, 170, 173, 175, 176, 181, 183, 186 potassium, 42, 69, 72, 73, 130, 155, 187 precursor cells, 92, 102 prefrontal cortex, 46, 52, 60 pregnancy, 17 premature death, 4 premature infant, 22, 33 preparation, iv, 111 pressure, 134, 136, 152 presynaptic, 127, 128, 130, 131, 132, 142, 145, 155, 156, 163, 164, 167, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 184, 185, 186, 187 prevention, 32, 33 primary brain tumor, 104 primary tumor, 94 probability, 44, 175 probe, 5, 14 prodrome, 47 producers, 23 production, 128, 132, 155, 183 progenitor cells, 92, 101 progesterone, viii, 2, 15, 16, 17, 31 prognosis, 103 pro-inflammatory, 150 project, 39, 127 proliferation, 71, 78, 94, 95, 96, 103, 104 proline, 103 propionic acid, 126, 131, 143 proposition, 174 propranolol, 13 prostaglandin, 154, 162 prostaglandins, 126, 150 prostate cancer, 95 proteases, 126 protection, 14, 24 protective factors, 88 proteins, x, 23, 24, 40, 41, 45, 46, 68, 69, 70, 75, 80, 84, 95, 106, 113, 121, 128, 130, 169, 171, 179, 181, 182, 183, 184 proteolipid protein, 92, 102 proteolytic enzyme, 3 protocols, 171 protons, 42 psoriasis, 89 psychiatric disorders, 55 psychiatry, 53 psychopathology, 47 psychoses, 4 psychosis, 42, 51, 57, 60 psychosocial functioning, 36

197

psychotic symptoms, 47, 58 pulmonary edema, 100 pulse, 159, 170 purines, 28 pyramidal, 129, 132, 154, 156, 162, 170, 173, 174, 175, 176, 177, 179, 180, 181, 182, 185, 187 pyramidal cells, 79, 123, 129, 132, 154, 156, 162, 175, 181, 182, 185, 187 pyramidale, 107

Q quality of life, 50 quantum dot, 84 quantum dots, 84

R radicals, 10, 18 radius, 75 rain, 154 ramp, 112, 114 raphe, 126, 137, 139, 140, 154, 168 rat, 134, 137, 141, 142, 145, 146, 147, 148, 149, 150, 151, 152, 154, 155, 156, 157, 158, 159, 161, 162, 163, 164, 165, 166, 167, 168, 184, 185, 186, 187 rats, 133, 134, 135, 136, 137, 139, 140, 145, 148, 151, 154, 159, 160, 162, 163, 165, 166, 168 reactive oxygen, 95 recall, 47 reciprocal interactions, 60 recognition, 47, 48, 116, 165 recommendations, iv recovery, 10, 11, 12, 13, 19, 31, 32, 33 recovery process, 19 recruiting, 41, 95 rectification, 113, 114, 115, 122 recurrence, 95 recycling, 36 red blood cells, 14, 20 redistribution, viii, 2, 14, 17, 19, 73, 113 reflexes, 166 reflexive responses, 133 regeneration, 89 regular, 129 regulation, 130, 157, 161, 162, 171, 177, 179, 181, 184, 185, 187 regulatory agencies, 38 relevance, 26, 27, 62, 119, 164 reliability, 8 relief, 155 remission, 8

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Index

renal failure, 7, 26 repair, 5, 89, 97 replication, 88 requirements, 58, 68, 187 researchers, 69, 137 residues, 155 resistance, 33 respiration, 40 respiratory arrest, 71 response, 10, 14, 17, 27, 29, 36, 56, 70, 72, 73, 75, 83, 88, 89, 92, 93, 106, 109, 112, 113, 124, 127, 130, 132, 133, 134, 135, 139, 140, 141, 142, 145, 148, 153, 160, 163, 165, 184 restrictions, 71 retardation, 47 retina, 62, 71, 166 reversal learning, 57 rheumatoid arthritis, 8, 16, 27, 89 ribose, 10, 100 rights, iv risk, 18, 30, 31, 48, 62 risk factors, 62 risperidone, 55 rodents, 13, 50, 59 root, 180, 182 rules, 57, 124, 184 ruthenium, 74, 77, 84

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S saccharin, 108 safety, viii, 2, 17, 47, 126, 153 salt, 144 saturation, 3 scaling, 43 scarcity, 115 scavengers, vii, viii, 1, 2, 4, 5, 6, 9, 20, 21 schizophrenia, vii, viii, 8, 27, 35, 36, 37, 38, 39, 40, 42, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 schizophrenic patients, 8, 27, 38, 39, 47, 49, 54, 55, 56, 57, 60 secretion, 15, 30, 50, 63, 70, 71, 77, 79, 80, 88, 93, 99, 100 sedation, 130 sedative, 130 sedatives, 129 seizure, 70 seizures, 185 selective serotonin reuptake inhibitor, 126, 152 selectivity, 131, 155, 157, 167 sensation, 127, 156 sensing, 174

sensitivity, 44, 74, 174, 175, 182 sensitization, 107, 119, 124, 136 sensorimotor gating, 48 sepsis, 18 septic shock, 18 septum, 91 serine, 26, 27, 37, 45, 48, 49, 50, 54, 55, 63, 64, 65, 123, 144 serotonergic, 152 serotonin, viii, 27, 35, 39, 49, 126, 152, 167 serum, 12, 25, 26, 31, 50, 54, 71, 121 services, iv sex, 15, 16 sex differences, 16 sex hormones, 15 shape, 10, 183 shares, 183 shock, 28, 75, 76, 85 short-term, 132, 185 short-term memory, 54 showing, 36, 117, 172, 173, 174 side effects, 38 signal transduction, 40, 41, 68 signaling, x, 125, 127, 129, 155, 156, 187 signaling pathway, 46, 93, 95, 97, 99 signalling, x, 23, 51, 77, 82, 85, 100, 102, 153, 169, 171, 172, 178, 179, 181, 182, 183, 185, 187 signals, 68, 92, 98, 126, 184 signs, 106 simulation, 52 siRNA, 95, 149 sites, x, 125, 126, 127, 129, 131, 133, 142, 145, 147, 165 skeletal muscle, 5, 7, 14, 15, 19, 20 skin, ix, 87, 88, 89, 126 social behavior, 48 society, 126 sodium, viii, 3, 28, 42, 52, 56, 67, 69, 72, 73, 128, 131, 144, 152 solution, 10, 11, 12, 77, 173 somata, 115 somatomotor, 162 spatial, 186 specialization, 127 species, 95, 147 specificity, 129, 154, 187 spectroscopy, 72 spectrum, 177 spinal cord, 28, 44, 49, 58, 59, 90, 126, 134, 149, 153, 155, 157, 161, 165, 166, 171, 182, 183 spinal cord stimulation, 165 spines, 130 squamous cell, 94, 95, 103

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Index squamous cell carcinoma, 94, 95, 103 stabilization, 45 state, 43, 47, 57, 77, 88, 118, 176 states, vii, 1, 33, 118, 164 staurosporine, 172 stellate cells, 160 steroids, 15, 30 stimulation, vii, 1, 3, 15, 20, 41, 45, 55, 71, 74, 77, 79, 96, 116, 124, 134, 141, 145, 153, 159, 162, 165, 170, 173, 179, 181, 183 stimulus, ix, 19, 105, 133, 134, 141, 145, 148, 174 stoichiometry, 69, 131 storage, 60 strength, 127 stress, viii, 2, 13, 14, 20, 26, 32, 52, 72, 126 stress response, viii, 2, 13, 14 striatum, 48, 52, 53, 54, 60, 64 stroke, vii, 1, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 18, 21, 22, 24, 25, 26, 29, 31, 33, 34, 69, 70, 71 stromal cells, 99 structure, 23, 41, 57, 59, 60, 61, 70, 97, 154, 155, 157, 161, 163 substitutions, 54 substrate, 30 substrates, 9, 124 suicide, 60 sulfate, 33 sulfonamide, 144 symptoms, viii, ix, 7, 8, 35, 36, 38, 39, 47, 48, 49, 50, 58, 59, 63, 67, 71, 72 synapse, 3, 37, 39, 55, 68, 79, 106, 113, 116, 118, 120, 126, 128, 146, 158, 172, 175, 176, 177, 178, 180, 181, 183, 186, 187 synapses, 127, 129, 130, 133, 146, 155, 156, 159, 162, 163, 164, 171, 173, 175, 176, 177, 178, 179, 180, 181, 185, 186, 187 synaptic plasticity, 36, 40, 41, 45, 51, 52, 57, 58, 61, 111, 122, 123, 124, 127, 132, 133, 158, 163, 178, 183 synaptic strength, 2, 43, 108, 118 synaptic transmission, 37, 40, 45, 46, 50, 57, 58, 60, 61, 63, 64, 98, 102, 103, 123, 127, 131, 132, 139, 154, 164, 166, 167, 171, 182, 184, 185 synaptic vesicles, 69, 70, 71, 77, 78 synaptogenesis, 171 synchronous, 174, 179 syndrome, 56, 71 synthesis, 4, 15, 72, 77, 95, 98, 100, 161, 186

T T lymphocytes, 93

199

tail-flick, 134, 135, 139, 140, 141, 142, 145, 150, 151, 152 tamoxifen, 75 tardive dyskinesia, 38 target, 36, 51, 55, 89, 90, 97, 103, 149, 157, 176, 183 targets, 149, 159, 176, 183 taste, 156 tau, 112 technical assistance, 119 techniques, 114, 116 temporal, 139 tension, 24, 77 terminals, 4, 36, 37, 44, 68, 70, 74, 76, 77, 79, 80, 81, 127, 130, 171, 172, 173, 176, 177, 178, 179, 182, 184 testing, 111 testis, ix, 87, 88, 99 thalamus, 154, 156, 160, 164 therapeutic agents, 38, 48, 50 therapeutic approaches, 24, 59, 153, 164 therapeutic benefits, 50 therapeutic effects, x, 125 therapeutic targets, 50, 53, 97 therapy, 8, 15, 29, 30, 31, 36, 49 thresholds, 136 thyroid, 20, 33, 94 time frame, 11 tissue, 3, 4, 27, 33, 68, 69, 78, 89, 90, 94, 95, 97, 100, 101, 133, 137, 167 tissue engineering, 100 tolerance, 153, 159, 160, 162 tonic, 39, 158, 176, 179, 185 topology, 171 toxic effect, viii, 2, 4 toxicity, 28, 62 toxin, 96, 170, 171, 172, 176, 177, 178, 180, 185, 187 trafficking, 45, 52, 54, 57, 58, 60, 122, 123, 124, 166, 183, 187 training, 33 transcription, 165 transcription factor, 165 transfer, 127, 156 transformation, 94 transgenic, 130, 147, 181, 183 transgenic mice, 130, 147, 181, 183 translational, 153 translocation, 90, 115 transmembrane region, 41 transmission, 37, 40, 45, 52, 68, 79, 84, 99, 122, 124, 127, 131, 132, 135, 139, 141, 154, 158, 162, 164, 166, 167, 168, 171, 172, 173, 174, 175, 179, 182, 183, 184, 185, 187

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Index

transport, vii, 1, 3, 20, 21, 23, 26, 51, 55, 69, 75, 76, 77, 79, 80, 81, 82, 95, 100, 128 transport processes, 77 trauma, 12, 18, 19, 28, 31 traumatic brain injury, vii, 1, 4, 24, 25, 28, 29, 31, 34 treatment, vii, ix, 2, 4, 7, 9, 10, 11, 12, 13, 15, 17, 18, 21, 22, 24, 25, 27, 31, 32, 34, 38, 45, 48, 54, 55, 56, 57, 62, 63, 67, 96, 105, 107, 108, 109, 110, 118, 152, 160 trial, 32, 60 tricyclic antidepressant, 152 triggers, 68, 78, 99, 102 tuberculosis, 49 tumorigenesis, 89 tumors, 95 turnover, 21, 33, 53 tyrosine, 77, 98, 127, 184

verbal fluency, 47 vesicle, 74, 76, 77, 83, 84 victims, 12, 21 vision, 155 vocalisations, 140, 148 vocalizations, 158 vulnerability, 47

W warrants, 183 water, 10, 71, 72, 73, 84, 108, 134 weakness, 72 wealth, 153 well-being, 126 workers, 74, 75, 137 wound healing, 88, 89, 90, 97

V

Y yeast, 61

Z zinc, 42, 43, 166

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valuation, 157 variables, 32 variations, 29 vasculature, 5 vasoactive intestinal peptide, 100 vasopressin, 71, 78, 79 vein, 21, 25 velocity, 91

Glutamate: Functions, Regulation and Disorders : Functions, Regulation and Disorders, Nova Science Publishers, Incorporated, 2012. ProQuest