Abstract
Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.
Highlights
L-glutamate (L-glu) is the major excitatory neurotransmitter in the brain and is functionally involved in virtually all activities of the nervous system
Upon depolarization of the presynaptic membrane, L-glu is released into the synaptic cleft and binds to ionotropic glutamate receptors at the postsynaptic membrane (Figure 1). iGluRs are ligand-gated ion channels and include receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartic acid (NMDA) types
In mice in which genetically engineered deletion of xCT leads to deficiency in the glutamate/cystine antiporter system x−c, the prominent reduction of extrasynaptic L-glu is associated with a robust resistance of dopaminergic neurons against 6hydroxydopamine-induced neurodegeneration (Massie et al, 2011), possibly as a result of decreased excitotoxicity
Summary
L-glutamate (L-glu) is the major excitatory neurotransmitter in the brain and is functionally involved in virtually all activities of the nervous system. We will first outline the general principles of L-glu signaling in the brain. We will broaden this scheme by expanding the model to (a) different pools of extracellular glutamate (synaptic, perisynaptic, and extrasynaptic) resulting from either vesicular and non-vesicular sources or atypically located glutamate receptors outside of synapses and (b) other molecules present in the brain that have the ability to activate glutamate receptors and discuss their possible physiological functions
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