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Because of its widespread abundance throughout the central nervous system and its complex role in several metabolic pathways, the function of glutamate as a neurotransmitter and its clinical significance have only recently been illuminated. Glutamate is now acknowledged as the principal excitatory neurotransmitter in the central nervous system. Clinically, aberrant glutamatergic activity has been associated with addiction, psychosis, neurodegeneration, and glial cell death. It has become a pharmacological target in many areas of disease research.[1]

Glutamate is of particular importance in several pathophysiological disease processes. Excitotoxicity induced by the sequential process of increased cytosolic Ca (calcium), subsequent activation of cytochrome c, and eventual apoptosis can be both acutely traumatic and chronically contributive to neurodegenerative diseases. Excitotoxicity not only damages neurons but also affects glial cells. Furthermore, damage incurred by each glial cell type manifests distinctly. Oligodendrocytes, which are very sensitive to excess glutamate, undergo apoptosis via an AMPA receptor-mediated process similar to that of neurons. Astrocytic injury potentiates glutamate dysregulation, and microglial injury can further impair neuronal glutamate uptake and receptor expression. Precipitant disease processes manifesting from aberrant glutamatergic excitotoxicity include Alzheimer disease, multiple sclerosis, amyotrophic lateral sclerosis, and more.[2][7] For these reasons, glutamate receptor expression and function, including that of GLT-1, have been identified as potential targets for pharmacological intervention.[9] Dysfunction of NMDA receptors and resultant glutamate dysregulation also has implications in the pathophysiology of schizophrenia, but the body of research regarding this topic is less robust. Although sparse in its application, NMDA-receptor antagonists have been administered as adjuncts in the treatment of schizophrenic patients.[10] The pathophysiology of addiction also involves glutamate, whose homeostatic cycling becomes dysregulated with chronic drug use. Eventually, this leads to a breakdown of communication between the prefrontal cortex and the nucleus accumbens and reinforces patterns of drug-seeking.[11] Outside the nervous system, glutamate may play a role in osmotic signaling that controls whole-body protein metabolism, which has important implications for skeletal muscle maintenance and cardiac function.[12]