Origin of Cortical Hyperexcitation in MeCP2-deficient Brain

MeCP2 缺陷大脑皮质过度兴奋的起源

基本信息

批准号：
8633913
负责人：
Zhong-Wei Zhang
金额：
$ 8.75万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8633913
关键词：
Acute Age Anxiety Behavior Behavioral Brain Brain Diseases Brain Part Brain region Chronic Clinical Data Cognitive Data Defect Development Electroencephalography Electrophysiology (science)Epilepsy Genes Goals Immunofluorescence Immunologic Knockout Mice Laboratories Life Methyl-CpG-Binding Protein 2 Monitor Motor Mus Mutant Strains Mice Mutation Neocortex Neurodevelopmental Disorder Neurologic Neurons Pathogenesis Patients Phenotype Physiological Physiology Prefrontal Cortex Property Prosencephalon Recurrence Research Rett Syndrome Role Seizures Series Slice Social Interaction Staining method Stains Symptoms Synapses Testing Work cell type cognitive function excitatory neuron genetic manipulation girls improved inhibitory neuron loss of function mutation mouse model nervous system disorder neurotransmission patch clamp public health relevance research study synaptic function transmission process treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Rett syndrome (RTT) is a severe neurodevelopmental disorder causing progressive loss of motor and cognitive functions, impaired social interactions, anxiety, and seizures in young girls. Mutations in the gene encoding MeCP2 (methyl-CpG binding protein 2) are the cause of RTT. It has been hypothesized that defects of neuronal circuit development and function are responsible for neurological symptoms of RTT. The majority of RTT patients have recurrent seizures, suggesting that hyperexcitation of the neocortex is a common feature of RTT. Consistent with clinical data, MeCP2-deficient mice also show cortical hyperexcitation and seizures. Besides epilepsy, hyperexcitation of the neocortex may have major roles in cognitive and behavioral defects of RTT. Reducing cortical hyperexcitation is a potential treatment strategy for RTT. However, mechanisms underlying cortical hyperexcitation in RTT are poorly understood. This application will test the hypothesis that loss of MeCP2 in excitatory neurons in the cortex causes hyperexcitation by downregulating GABAergic transmission in the cortex. In testing this hypothesis, we take advantage of genetic manipulation in the mouse, electrophysiology, and our expertise in physiology and development of cortical neurons. The two specific aims are: 1) to determine the role of MeCP2 in regulating inhibitory neurotransmission in the cortex; and 2) to investigate of the effects of MeCP2 deficiency on cortical excitability and seizures.

项目摘要/摘要 RETT综合征（RTT）是一种严重的神经发育障碍，导致运动和认知的进行性丧失年轻女孩的功能，社交互动受损，焦虑和癫痫发作。基因编码中的突变 MECP2（甲基-CPG结合蛋白2）是RTT的原因。已经假设神经元电路的发育和功能负责RTT的神经系统症状。大多数 RTT患者复发性癫痫发作，表明新皮层的过度刺激是 RTT。与临床数据一致，MECP2缺陷型小鼠还显示出皮质过度刺激和癫痫发作。除癫痫外，新皮层的过度刺激可能在认知和行为缺陷中具有重要作用 RTT。减少皮质过度刺激是RTT的潜在治疗策略。但是，机制 RTT中的潜在皮质过度刺激知之甚少。该应用程序将检验以下假设皮质中兴奋性神经元中MECP2的丧失通过下调GABA能引起过度刺激在皮质中的传输。在检验这一假设时，我们利用小鼠中的遗传操纵，电生理学以及我们在皮质神经元生理学和发育方面的专业知识。两个具体目标为：1）确定MECP2在调节皮层中抑制性神经传递中的作用；和2）到研究MECP2缺乏对皮质兴奋性和癫痫发作的影响。