Glutamate is the most abundant excitatory neurotransmitter, present at up to 80-90% 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 10 millimolar intracellular concentrations in brain, contributing to anti-oxidant and anti-inflammatory defense. Because of the substantial amounts of brain glutathione and its rapid turnover, we hypothesized that glutathione is a relevant reservoir of glutamate, and could influence synaptic excitability. We find that diminishing the liberation of glutamate by the glutathione cycle produces decreases in cytosolic glutamate, decreased frequency of miniature excitatory post synaptic potentials (mEPSC), and diminished depolarizationassociated calcium flux. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate, increased frequency of mEPSC, and increased depolarization-associated calcium release. 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 that bridges anti-inflammatory pathways and glutamatergic functioning.
Glutathione shapes glutamateric transmissionAll rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/325530 doi: bioRxiv preprint first posted online May. 18, 2018;
INTRODUCTIONGlutamate is the most abundant excitatory transmitter in the central nervous system, utilized at 50-70% of cortical synapses.1, 2 Glutamate participates in diverse physiological processes, such as developmental plasticity and long-term potentiation as well as brain diseases:epilepsy, stroke, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and schizophrenia. 3 Glutathione is a tripeptide of glutamate, cysteine and glycine, occurring in neurons at concentrations of 2-10 mM; it is the most abundant low molecular weight thiol of bacteria, plant and animal cells. [4][5][6] As such, it regulates critical cellular processes such as metabolism of estrogens, prostaglandins, leukotrienes and xenobiotic drugs. Glutathione is well known as an anti-oxidant agent, providing a major line of defense against oxidative and other forms of stress, largely as a cofactor for the glutathione peroxidase and S-transferase enzyme families. [7][8][9][10] Glutathione metabolism is governed by the glutathione cycle ( Supplementary Figure 1), in which glutamate is added and liberated at discrete steps. 4, 11 Glia serve as a major supplier of cysteine for neuronal glutathione synthesis, and 50-60% of glutamate neurotransmitter is derived from the glutamine-glutamate shuttle between neurons and glia, with substantially smaller amounts of glutamate ...