Year: 2019
Type: article
Abstract: Glutamate is the most abundant excitatory neurotransmitter, present at the bulk of cortical synapses, and participating in many physiologic and pathologic processes ranging from learning and memory to stroke. The tripeptide, glutathione, is one third glutamate and present at up to low millimolar intracellular concentrations in brain, mediating antioxidant defenses and drug detoxification. Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate, and could influence synaptic excitability. We find that drugs which inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory post synaptic potential (mEPSC) frequency. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate and enhanced mEPSC frequency. The glutathione cycle can compensate for decreased excitatory neurotransmission when the glutamate-glutamine shuttle is inhibited. Glutathione may be a physiologic reservoir of glutamate neurotransmitter. Significance Glutathione is the principal antioxidant and redox regulator in cells. In addition to its essential roles in redox homeostasis it functions as cofactors for a multitude of enzymes. We show here that glutathione is a reservoir for synaptic glutamate, the excitatory neurotransmitter in the central nervous system. Deficits in glutathione have been linked to multiple neurodegenerative and neuropsychiatric disorders. Accordingly, agents that restore glutathione-glutamate homeostasis may afford therapeutic benefit.
Institutions: Johns Hopkins University, Johns Hopkins Medicine
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
Funders: Johns Hopkins University, National Alliance for Research on Schizophrenia and Depression, Brain Science Institute, Johns Hopkins University, National Institutes of Health, U.S. Public Health Service, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke
Awards: G146009994, G2415693321, G2527769453, G2802054596, Neurochemical Actions of Psychotropic Drugs, G3959970969, G4408913484, G4708149158, G4843311177, G5119514285, G5165752122, G5235451531, G5437238147, G5512383668, G5812696834, G6541910801, G7765072668, G800738591, G817875007, Gene-Environment Interactions for Cortical Development and Schizophrenia, G8794121922, G8804537486, Neurochemical Actions of Psychotropic Drugs, G9000003855, G9000005924, G9000021114, G9000026641, G9000116404, G9000163564, G913113481
OpenAlex ID: W2912617835