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