Review
The role of glutamate in central nervous system health and disease – A review

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Abstract

Glutamate is the principal excitatory neurotransmitter in the brain. Knowledge of the glutamatergic synapse has advanced enormously over the last 10 years, primarily through application of cellular electrophysiological and molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic glutamate receptors with intrinsic cation permeable channels. There are also three groups of metabotropic, G-protein-coupled glutamate receptors that can modify neuronal excitability. There are also two glial glutamate transporters and three neuronal transporters in the brain. Endogenous glutamate may contribute to the brain damage occurring acutely after traumatic brain injury as well as having a role in the excitatory imbalance present in epileptic conditions and contributing to the pathophysiology of hepatic encephalopathy in animals. Understanding the role of glutamate in these neurological diseases may highlight treatment potentials of antagonists to glutamatergic transmission. This paper presents a review of the literature of glutamate and its role in neurological function and disease.

Introduction

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). In addition to its immediate impact as an excitatory amino acid, it has a role in long-term neuronal potentiation, as a proposed molecular substrate for learning and memory (Attwell, 2000, Meldrum, 2000, Tapiero et al., 2002, Tzschentke, 2002). Glutamate acts mainly post-synaptically on three families of ionotropic (ligand-gated ion channels) receptors, (Meldrum, 2000, Tapiero et al., 2002) which all possess ion channels that are permeable to cations, although the relative permeability to Na+ and Ca2+ varies according to the family and the subunit composition of the receptor (Attwell, 2000, Meldrum, 2000). Glutamate may also be a potent neurotoxin, and glutamate excitotoxicity has been implicated in the pathogenesis of many devastating human neurological diseases such as stroke, amyotrophic lateral sclerosis and epilepsy (Smith, 2000). In veterinary medicine, it is likely that glutamate plays a pivotal role in the pathophysiology of several neurological diseases including epilepsy, acute CNS trauma and hepatic encephalopathy.

Section snippets

Glutamate synthesis, release and uptake

Glutamate is found throughout the mammalian brain and participates in many metabolic pathways (Attwell, 2000, Petroff, 2002). Glutamine and α-ketoglutarate are thought to be the major precursors of glutamate, which is subsequently packaged into vesicles for future release into the synaptic cleft (Tapiero et al., 2002). Glutamine is taken up into the pre-synaptic terminal via an active, Na+-dependent uptake protein (Anderson and Swanson, 2000, Daikhin and Yudkoff, 2000). It is then transported

Excitatory amino acid hypothesis

Few concepts in modern neurobiology have generated as much interest as the view that the excessive release of excitatory amino acids results in the proliferation of neuronal damage. The major assumption of this hypothesis is that the release of excessive neurotransmitters, as exemplified by glutamate, follows a variety of insults, including trauma, and that excessive accumulation of excitatory amino acids initiates a complex process of cellular injury, which, if uninterrupted, will result in

The role of glutamate in epilepsy

Epileptic syndromes have very diverse primary causes, which may be genetic, developmental or acquired (McNamara, 1994). During an epileptic seizure, large populations of neurons in selected portions of the central nervous system abandon their normal activity and begin to fire in periodic synchronous discharges. This pathological synchronized activity is transmitted from one neuron to the next primarily through excitatory glutamatergic transmission, although GABA-ergic synapses also shape

CNS injury

Primary traumatic brain injury is a direct result of the initial insult, is complete at the time of presentation, and cannot be altered. Secondary traumatic brain injury is an alteration of brain tissue, either anatomic or physiologic, which occurs subsequent to the primary injury (Leonard and Kirby, 2002). Secondary injury may include oedema and elevations of intracranial pressure (Chen and Swanson, 2003). Traumatic brain injury has been shown to cause marked elevation in glutamate

Hepatic encephalopathy

A large body of evidence has accrued demonstrating a disturbance of glutamatergic neurotransmission in hepatic encephalopathy (HE) (Hazell and Butterworth, 1999). HE is a severe neuropsychiatric complication of both acute and chronic liver failure (Jones and Weissenborn, 1997).

An overall decrease in brain glutamate is found in several animal models of portosystemic encephalopathy (PSE) and acute liver failure (de Knegt et al., 1994, Oppong et al., 1995). Glutamine synthetase activity, which is

Summary

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It has the potential to be involved in the pathogenesis of many CNS diseases either due to excessive release, reduced uptake or alteration of receptor function. With the increasing knowledge about the role of glutamate in the health and disease of the nervous system, it is possible that it will serve as an important marker for disease and target for treatment in veterinary neurology.

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