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

了解 CNS 兴奋/抑制平衡和系统 xc- 的性别二态作用

• 批准号: 10187769
• 负责人: Carla Frare
• 金额: $ 6.78万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187769
• 关键词: Acute; Age; Amino Acids; Behavioral; Biological; Brain; Breeding; Cell membrane; Cellular Morphology; Clinical; Cognitive; Collaborations; Communication; Cystine; Data; Dendrites; Development; Disease; Electroencephalogram; Electroencephalography; Electrophysiology (science); Environment; Epilepsy; Equilibrium; Exposure to; Fellowship; Female; Glutamate Receptor; Glutamates; Impaired cognition; In Vitro; Injury; Kainic Acid; Knockout Mice; Maintenance; Measurement; Measures; Medical; Mentors; Mentorship; Modeling; Molecular; Morphology; Motor; Motor Cortex; Mus; National Institute of Neurological Disorders and Stroke; Neuraxis; Neurodevelopmental Disorder; Neurologic; Neurons; Neurosciences Research; Operative Surgical Procedures; Oral; Phase; Phenotype; Physiological; Policies; Procedures; Process; Property; Public Health; Pyramidal Cells; Reporting; Research; Research Design; Research Training; Resources; Role; Schizophrenia; Sex Differences; Signal Transduction; Slice; Statistical Data Interpretation; Status Epilepticus; Stroke; Subclinical Seizures; Synapses; Synaptic Membranes; Synaptic plasticity; System; Technical Expertise; Techniques; Testing; Training; Traumatic Brain Injury; Universities; Vertebral column; Wild Type Mouse; antiporter; autism spectrum disorder; behavior test; behavioral impairment; behavioral phenotyping; brain electrical activity; career; improved; in vivo; interest; kainate; male; mortality; nervous system disorder; neuronal cell body; neurotransmission; novel therapeutics; null mutation; postsynaptic; prevent; receptor; response; sex; sexual dimorphism; skills

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.

一个健康的大脑需要兴奋性/抑制性(E/I)平衡，E/I平衡的改变有助于神经和神经发育障碍和疾病(如中风、癫痫和自闭症)的病理生物学。需要对调节生理E/I平衡的细胞和分子机制有更深入的了解，以改进目前临床上处理E/I扰动的策略。我们实验室的最新证据表明，质膜异源二聚体氨基酸半胱氨酸/谷氨酸逆向转运蛋白系统XC-(SXC-)有助于维持体内神经元的E/I平衡。具体地说，我们发现，与野生型小鼠相比，雄性和雌性SXC基因缺失小鼠(SLC7a11sut/sut)在急性全身注射化学惊厥剂海人藻酸盐时都表现出行为过度兴奋的表型。这种性别无关的超兴奋表型伴随着性别相关的形态变化，这些变化以前曾被认为与网络兴奋性的增加有关。这些观察结果导致了一个有趣的假设，将在Aim1中进行充分探索，即在幼稚的SLC7a11sut/sut小鼠中发现的形态性别差异是性别无关的过度兴奋的基础，最终导致认知行为障碍。相反，长期服用红藻氨酸(一种用于诱发癫痫持续状态的亚急性范例)会导致雄性和雌性SLC7a11sut/sut小鼠的行为兴奋性低下，与性别匹配的SLC7a11+/+(野生型)小鼠的情况相反。因此，目的2研究在长时间刺激后，SLC7a11sut/sut小鼠的神经元中是否发生非性别的兴奋性突触后受体的下调。杂合子小鼠的室内繁殖允许雄性和雌性SLC7a11sut/sut和SLC7a11+/+窝产仔用于每个目的。在这两个目标中，将通过体内脑电记录来检测兴奋性的变化，以测量多突触脑电活动的变化，并在体外进行电生理学，以确定在幼稚的SLC7a11sut/Sut小鼠(目标1)中存在的高兴奋性表型背后的相关突触变化，以及在KA范式完成时的低兴奋性表型(目标2)。这些目标的成功完成将提供关于SXC-在E/I平衡和失衡中的性二型性作用的重要机制信息。奖学金培训计划包括严格的技术培训(电生理学、脑电无线电遥测、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)，分别在赞助商和联合赞助商位于锡拉丘兹大学和纽约州立大学北部医科大学的研究实验室进行，遵守NINDS Rigor报告制定的政策和程序。苏州理工大学和两所大学之间丰富、协作的神经科学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。