Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo

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PROJECT SUMMARY In several brain disorders including epilepsy, stroke and traumatic brain injury, an imbalance between the excitatory and inhibitory (E/I) neurotransmitter systems exists. Understanding fully the cellular and molecular processes that underlie normal, physiological transmission is the first step in determining how aberrations of such might be countered to provide such individuals with E/I imbalance symptomatic relief. Recent evidence from our lab demonstrates a role for the cystine/glutamate antiporter System xc- (Sxc-) ─ which exports glutamate and imports cystine, the latter of which is the rate-limiting substrate for the synthesis of the thiol antioxidant glutathione ─ in maintenance of E/I balance. Specifically, we find that sut/sut mice, which harbor a natural mutation in SLC7a11 (SLC7a11sut/sut) and are therefore devoid of Sxc-, are considerably more hyperexcitable than their wild-type littermates upon acute challenge with kainic acid or pentylenetetrazole. Paradoxically, after repeated sub-acute/sub-chronic administration of the same chemoconvulsants, SLC7a11sut/sut mice exhibit signs of hypoexcitability, a response polar opposite to that which occurs in wild-type littermate controls. The idea that these paradoxical findings may result from the same underlying mechanism ─ namely synaptic scaling ─ will be explored in this proposal. State-of-the-art in vivo sensor technology, as well as, cellular, molecular and pharmacological approaches will be used to test the hypothesis that chronic loss of Sxc- leads to a scaling up of glutamate receptors under basal conditions, whereas scaling down occurs under conditions of enhanced neuronal activity ─ both in efforts to stabilize neuronal firing. Whether these finding are mediated by changes in glutamate and/or glutathione will also be explored. Studies to determine the cellular specificity of response, with specific focus on the role of the astrocyte, are also planned. Overall, these studies are designed to increase our mechanistic understanding of the contribution of astrocyte Sxc- to glutamate, glutathione and activity homeostasis in in vivo brain. More broadly, these efforts complement other ongoing efforts to identify targets to treat the E/I imbalance that exists in many neurological disorders.