MeCP2 and GABAergic Transmission

MeCP2 和 GABA 能传输

基本信息

批准号：
7658575
负责人：
Zhong-Wei Zhang
金额：
$ 8.7万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7658575
关键词：
Acute Age Age-Months Anatomy Brain Brain region Cells Complex Defect Development Electrophysiology (science)Equilibrium Foundations Future Genes Goals Histocytochemistry Inhibitory Synapse Knock-out Knockout Mice Label Language Life Link Mediating Methyl-CpG-Binding Protein 2 Molecular Molecular Target Motor Mus Mutant Strains Mice Mutation Neurons Onset of illness Pathogenesis Patients Pattern Phenotype Play Probability Regulation Research Rett Syndrome Role Slice Symptoms Synapses System Thalamic Nuclei Thalamic structure Ventral Nuclear Group Wild Type Mouse base excitatory neuron girls improved inhibitory neuron loss of function mutant nerve supply nervous system disorder patch clamp postnatal public health relevance public health research reconstruction research study skills synaptic function transmission process vesicular GABA transporter

项目摘要

DESCRIPTION (provided by applicant): Rett syndrome (RTT) is a severe neurological disorder causing progressive loss of motor and language skills in girls. Mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) and the loss of MeCP2 function in the brain are the primary cause of RTT. Mecp2-knockout (Mecp2-null) mice and those with truncated MeCP2 recapitulate many features of RTT, and the phenotype in these mice is caused by MeCP2 deficiency in the brain. The lack of change in brain cytoarchitecture in RTT patients and MeCP2 mutant mice suggests that subtle changes in neuronal and synaptic functions are the primary cause. MeCP2 is highly expressed in both excitatory and inhibitory neurons in the brain. While recent studies have demonstrated a key role for MeCP2 in excitatory transmission, little is known about the role of MeCP2 in the development and function of inhibitory synapses. Our preliminary studies demonstrated that GABAergic transmission is significantly altered in the thalamus of Mecp2-null mice. Most interestingly, we found that GABAergic transmission is altered in opposite directions in excitatory and inhibitory neurons. We hypothesize that MeCP2 plays an important role in the development of GABAergic synapses in the thalamus. We will examine this hypothesis using a combination of electrophysiology, anatomy, and immuno- histochemistry in Mecp2-null mice. The two specific aims are to 1) determine changes in GABAergic transmission in the thalamus of Mecp2-null mice during postnatal development; and 2) determine structural basis for GABAergic defects in the thalamus. PUBLIC HEALTH RELEVANCE: This research will advance our understanding of the pathogenesis of Rett syndrome, and may provide opportunity for the development of new and improved treatments.

描述（由申请人提供）：雷特综合征（RTT）是一种严重的神经系统疾病，导致女孩逐渐丧失运动和语言技能。编码甲基 CpG 结合蛋白 2 (MeCP2) 的 X 连锁基因突变和大脑中 MeCP2 功能的丧失是 RTT 的主要原因。 Mecp2 敲除（Mecp2-null）小鼠和 MeCP2 截短的小鼠重现了 RTT 的许多特征，这些小鼠的表型是由大脑中 MeCP2 缺陷引起的。 RTT 患者和 MeCP2 突变小鼠的脑细胞结构缺乏变化表明神经元和突触功能的细微变化是主要原因。 MeCP2 在大脑的兴奋性和抑制性神经元中高度表达。虽然最近的研究证明了 MeCP2 在兴奋性传递中的关键作用，但人们对 MeCP2 在抑制性突触的发育和功能中的作用知之甚少。我们的初步研究表明，Mecp2 缺失小鼠的丘脑中 GABA 能传输显着改变。最有趣的是，我们发现兴奋性和抑制性神经元中的 GABA 能传递以相反的方向改变。我们假设 MeCP2 在丘脑 GABA 能突触的发育中发挥重要作用。我们将结合电生理学、解剖学和免疫组织化学在 Mecp2 缺失小鼠中检验这一假设。这两个具体目标是 1) 确定 Mecp2-null 小鼠在出生后发育过程中丘脑中 GABA 能传递的变化； 2) 确定丘脑 GABA 能缺陷的结构基础。公共健康相关性：这项研究将增进我们对雷特综合征发病机制的理解，并可能为开发新的和改进的治疗方法提供机会。