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

基本信息

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
项目类别：
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

项目摘要

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.

健康的大脑需要兴奋/抑制 (E/I) 平衡，E/I 平衡的改变有助于对神经和神经发育障碍和疾病（即中风、癫痫和自闭症）的病理生物学有更深入的了解调节的细胞和分子机制。我们实验室的最新证据表明，异二聚质膜氨基酸胱氨酸/谷氨酸逆向转运蛋白 System xc- 需要生理 E/I 平衡来改善当前的 E/I 扰动临床策略。 (Sxc-)，有助于维持体内神经 E/I 平衡。具体来说，我们发现雄性和雌性 Sxc-null 小鼠 (SLC7a11sut/sut) 在急性全身施用化学惊厥红藻氨酸后表现出行为过度兴奋表型。与它们的野生型同窝动物相比，这种与性别无关的过度兴奋表型伴随着性别依赖性的形态变化，这些变化先前被认为与网络兴奋性的增加有关。有趣的假设将在 Aim1 中得到充分探讨，即在幼稚 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，最终导致行为障碍，相反，更长时间的红藻氨酸给药（使用的亚急性范例）。诱导癫痫持续状态）导致雄性和雌性 SLC7a11sut/sut 小鼠行为兴奋性低下，与性别匹配的情况相反因此，Aim 2 研究了在长时间兴奋后，SLC7a11sut/sut 小鼠的神经元中是否会发生与性别无关的兴奋性突触后受体的下调，从而使雄性和雌性 SLC7a11sut/ 小鼠都能发生这种情况。 sut 和 SLC7a11+/+ 同窝动物用于每个目标中，兴奋性发生变化。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，以识别幼稚 SLC7a11sut/sut 小鼠超兴奋表型背后的相关突触变化（目标 1），以及完成时的低兴奋表型KA 范式（目标 2）的成功完成将提供有关 Sxc-in 的性别二态性作用的重要机制信息。 E/I 平衡和不平衡培训计划包括在申办者和共同申办者的研究实验室进行严格的技术（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）。雪城大学和纽约州立大学上州医科大学分别遵守 NINDS 严格报告规定的政策和程序，SU 本身以及两所大学之间丰富的合作神经科学研究环境将为候选人提供帮助。拥有各种研究培训和资源，以及成功过渡到学术研究职业所需的重要专业发展机会。