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The mechanistic basis for this hypothesis lies in the structure of the γ-glutamyl cycle: because GSH is one-third glutamate by composition and is present in neurons at millimolar concentrations with a relatively short half-life, pharmacological inhibition of enzymes that liberate glutamate from the cycle (GGT and OPLAH) reduces intracellular neuronal glutamate levels by 25–50% and suppresses miniature excitatory postsynaptic potential (mEPSC) frequency in primary cortical neurons, while inhibition of GSH biosynthesis has the opposite effect — elevating cytoplasmic glutamate and enhancing mEPSC frequency [52]
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