The glutathione cycle shapes synaptic glutamate activity

Thomas W. Sedlak, Bindu D. Paul, Gregory M. Parker, Lynda D. Hester, Adele M. Snowman, Yu Taniguchi, Atsushi Kamiya, Solomon H. Snyder, Akira Sawa

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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 that inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory postsynaptic potential (mEPSC) frequency. In contrast, pharma-cologically 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.

Original languageEnglish (US)
Pages (from-to)2701-2706
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
StatePublished - Feb 12 2019


  • Acivicin
  • Glutamate
  • Glutathione
  • Neurotransmission

ASJC Scopus subject areas

  • General


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