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

健康的大脑需要兴奋性/抑制性（E/I）平衡，而E/I平衡的改变有助于神经和神经发育障碍和疾病（即中风、癫痫和自闭症）的病理生物学。需要更深入地了解调节生理E/I平衡的细胞和分子机制，以改善当前管理E/I扰动的临床策略。我们实验室最近的证据表明，异二聚体质膜氨基酸胱氨酸/谷氨酸反转运体系统xc- (Sxc-)有助于维持体内神经元E/I平衡。具体来说，我们发现雄性和雌性Sxc-缺失小鼠（SLC7a11sut/sut）在急性全身给药后表现出一种行为过度兴奋的表型，与野生型小鼠相比。这种性别无关的过度兴奋表型伴随着性别依赖的形态变化，这些变化先前与网络兴奋性增加有关。这些观察结果导致了一个有趣的假设，在Aim1中得到了充分的探索，即naïve SLC7a11sut/sut小鼠中发现的形态性别差异是性别独立的过度兴奋性的基础，最终导致认知行为障碍。相比之下，更长时间的kainate（一种用于诱导癫痫持续状态的亚急性范式）会导致雄性和雌性SLC7a11sut/sut小鼠的行为低兴奋性，与性别匹配的SLC7a11+/+（野生型）小鼠相反。因此，Aim 2研究了SLC7a11sut/sut小鼠的神经元在长时间兴奋后，兴奋性突触后受体是否发生性别无关的降尺度。杂合小鼠的内部繁殖允许雄性和雌性SLC7a11sut/sut和SLC7a11+/+仔鼠在每个目标中使用。在这两个目的中，兴奋性的变化将通过体内脑电图记录来检测，以测量多突触脑电活动的变化，以及体外电生理学，以确定naïve SLC7a11sut/sut小鼠过度兴奋表型（Aim 1）的相关突触变化，以及ka范式完成时的低兴奋表型（Aim 2）。成功完成这些目标将提供重要的机制信息，关于性别二态作用的Sxc-在E/I平衡和不平衡。奖学金培训计划包括严格的技术培训（电生理学、脑电图无线电遥测、行为测试）和专业培训（口头/书面交流、统计分析、研究设计、指导），分别在锡拉丘兹大学和纽约州立大学上州医科大学的赞助商和共同赞助商的研究实验室进行，并遵守NINDS严密性报告规定的政策和程序。加州大学和两所大学之间丰富的神经科学合作研究环境将为候选人提供各种研究培训和资源，以及成功过渡到学术研究生涯所需的基本专业发展机会。

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.