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Elucidating the Function of Class 4 Semaphorins in GABAergic Synapse Formation

阐明 4 类信号蛋白在 GABA 能突触形成中的功能

基本信息

批准号：
8468221
负责人：
SUZANNE PARADIS
金额：
$ 32.51万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468221
关键词：
Address Autistic Disorder Binding Biochemical Biological Assay Brain CD100 antigen Candidate Disease Gene Cells Cognitive Communication Complex Defect Development Disease Epilepsy Equilibrium Excitatory Synapse Functional disorder Genetic Glutamates Goals Hippocampus (Brain)Image Impairment Inhibitory Synapse Injection of therapeutic agent Knowledge Learning Mediating Membrane Memory Mental Retardation Molecular Nervous system structure Neuraxis Neurologic Neurons Play Presynaptic Terminals Process Proteins RNA Interference Research Role Semaphorins Signal Transduction Site Speech Staging Structure Subfamily lentivirinae Synapses Techniques Time Wild Type Mouse autism spectrum disorder autocrine base density immunocytochemistry in vivo insight knock-down nervous system disorder neural circuit neurotransmitter release novel paracrine postsynaptic programs public health relevance receptor research study small hairpin RNA synaptic function synaptogenesis tissue fixing

项目摘要

DESCRIPTION (provided by applicant): Synapses are specialized sites of cell-cell contact that mediate communication between neurons in the nervous system. Much remains to be discovered about the molecular mechanisms that underlie formation of these critical structures in the mammalian central nervous system. While recent advances have contributed to our understanding of excitatory synapse formation, the processes that mediate inhibitory synapse formation remain poorly defined. In addition, it is hypothesized that aberrant synapse formation and function contributes to neurological disorders such as mental retardation, autism spectrum disorders and epilepsy. To appreciate how synapse dysfunction contributes to these widespread neurological impairments, it is important to first understand how synapses are formed, maintained, and function in the non-pathological state. To this end, we developed a novel, forward genetic RNA interference (RNAi)-based screen in cultured hippocampal neurons that has identified new molecules required for synapse formation. Using this technique, we discovered that RNAi-mediated knockdown of a class 4 Semaphorin, Sema4D, led to a decrease in the density of inhibitory synapses without an apparent effect on excitatory synapse formation. Thus, Sema4D is one of only a few molecules identified thus far that preferentially regulates inhibitory synapse formation. Further, Sema4D appears to be playing a specific role in assembling the postsynaptic specialization at inhibitory synapses. Therefore, understanding the mechanism of action of Sema4D in this process promises to yield key insights into the assembly of inhibitory synapses in the mammalian central nervous system.

描述（由申请人提供）：突触是细胞与细胞接触的特殊部位，介导神经系统中神经元之间的通信。关于哺乳动物中枢神经系统中这些关键结构形成的分子机制还有很多有待发现。虽然最近的进展有助于我们对兴奋性突触形成的理解，但介导抑制性突触形成的过程仍然不清楚。此外，据推测异常的突触形成和功能会导致神经系统疾病，例如智力低下、自闭症谱系障碍和癫痫。为了了解突触功能障碍如何导致这些广泛的神经损伤，首先了解突触在非病理状态下如何形成、维持和发挥作用非常重要。为此，我们在培养的海马神经元中开发了一种新型的、基于正向遗传 RNA 干扰 (RNAi) 的筛选，该筛选已识别出突触形成所需的新分子。利用这项技术，我们发现 RNAi 介导的 4 类信号蛋白 Sema4D 敲低会导致抑制性突触密度降低，但对兴奋性突触形成没有明显影响。因此，Sema4D 是迄今为止确定的少数优先调节抑制性突触形成的分子之一。此外，Sema4D 似乎在抑制性突触的突触后特化组装中发挥着特定的作用。因此，了解 Sema4D 在此过程中的作用机制有望对哺乳动物中枢神经系统中抑制性突触的组装产生重要的见解。