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

> **NIH NIH R01** · SYRACUSE UNIVERSITY · 2020 · $347,234

## Abstract

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.

## Key facts

- **NIH application ID:** 9874010
- **Project number:** 5R01NS105767-03
- **Recipient organization:** SYRACUSE UNIVERSITY
- **Principal Investigator:** SANDRA J HEWETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,234
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9874010

## Citation

> US National Institutes of Health, RePORTER application 9874010, Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo (5R01NS105767-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9874010. Licensed CC0.

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