Understanding CNS Excitatory / Inhibitory Balance and the Sexually Dimorphic Role of System xc-

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A healthy brain requires excitatory/inhibitory (E/I) balance and alterations in E/I balance contribute to the pathobiology of neurological and neurodevelopmental disorders and disease (i.e. stroke, epilepsy and autism). A deeper understanding of the cellular and molecular mechanisms regulating physiological E/I balance is needed to improve current clinical strategies for managing E/I perturbations. Recent evidence from our lab demonstrates that the heterodimeric plasma membrane amino acid cystine/glutamate antiporter, System xc- (Sxc-), contributes to the maintenance of neuronal E/I balance in vivo. Specifically, we find that both male and female Sxc- null mice (SLC7a11sut/sut) demonstrate a behavioral hyperexcitable phenotype upon acute systemic administration of the chemoconvulsant kainate, as compared to their wild-type littermates. This sex-independent hyperexcitable phenotype is accompanied by sex-dependent morphological changes that have been previously associated with increased network excitability. These observations led to the intriguing hypothesis, to be fully explored in Aim1, that the morphological sex differences found in naïve SLC7a11sut/sut mice underlie the sex-independent hyperexcitability, ultimately leading to cognitive behavioral impairment. In contrast, more prolonged administration of kainate (a subacute paradigm used to induce status epilepticus) results in behavioral hypoexcitability in both male and female SLC7a11sut/sut mice, the opposite from what occurs in sex-matched SLC7a11+/+ (wildtype) mice. Thus, Aim 2 investigates whether, after prolonged excitation, sex-independent downscaling of excitatory postsynaptic receptors occurs in neurons of SLC7a11sut/sut mice. In-house breeding of heterozygous mice allows both male and female SLC7a11sut/sut and SLC7a11+/+ littermates to be used in each aim. In both aims, changes in excitability will be detected by in vivo EEG recording, to measure changes in polysynaptic electrical brain activity, and in vitro electrophysiology, to identify the associated synaptic changes underlying the hyperexcitable phenotype in naïve SLC7a11sut/sut mice (Aim 1), and the hypoexcitable phenotype at completion of the KA-paradigm (Aim 2). Successful completion of these aims will provide important mechanistic information concerning the sexually dimorphic role of Sxc- in E/I balance and imbalance. The fellowship training plan includes rigorous technical (electrophysiology, EEG radiotelemetry, behavioral testing) and professional training (oral/written communication, statistical analysis, research design, mentorship) in the sponsor and co-sponsor’s research labs at Syracuse University and SUNY Upstate Medical University, respectively, that adheres to the policies and procedures laid down by the NINDS Rigor report. The rich, collaborative neuroscience research environment at SU proper and between the two universities will provide the candidate with varied research training and resources, and essential professional development opportunities needed for successful transition to an academic research career.