Cellular and molecular mechanisms underlying the function of SRGAP2 during synaptic development

突触发育过程中 SRGAP2 功能的细胞和分子机制

基本信息

批准号：
9328162
负责人：
FRANCK POLLEUX
金额：
$ 62.13万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2010-03-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9328162
关键词：
Address Area Behavior Behavioral Binding Binding Sites Biochemical Biological Brain Cells Complement Complex Development Electrophysiology (science)Equilibrium Evolution Excitatory Synapse Funding GABA-A Receptor Gene Duplication Genes Glutamate Receptor Homeostasis Homer 1 Human Inhibitory Synapse Knockout Mice Mammals Molecular Mus Neocortex Neurodevelopmental Disorder Neurons Performance Physiological Play Point Mutation Population Property Proteins Proteomics Publishing Rabies virus Role SH3 Domains SRGAP2 gene Sampling Scaffolding Protein Schizophrenia Slice Specificity Synapses Synaptic Receptors Synaptic plasticity Testing Transgenic Mice Vertebral column autism spectrum disorder cell type cognitive function density duplicate genes gene replacement gephyrin hippocampal pyramidal neuron human embryonic stem cell in vivo in vivo imaging interdisciplinary approach mouse model neocortical neural circuit neurogenesis paralogous gene postsynaptic presynaptic reconstruction scaffold synaptogenesis two-photon

项目摘要

ABSTRACT During development, tightly regulated mechanisms establish the proper balance between excitatory (E) and inhibitory (I) synaptic inputs made onto each neuronal cell type. Several neurodevelopmental disorders are thought to have emerged from E/I synaptic imbalance including autism spectrum disorders (ASD) and schizophrenia. However, the mechanisms coordinating excitatory and inhibitory synaptic development are still poorly understood. We recently discovered that SRGAP2 is a postsynaptic protein playing key roles in vivo in promoting the rate of excitatory and inhibitory synapses maturation and limiting the density of both types of synapses made onto pyramidal neurons in the developing cortex. In the previous funding period, we first made significant progress in dissecting the molecular mechanisms underlying SRGAP2 function at both excitatory and inhibitory synapses, discovering that its ability to promote excitatory synaptic maturation requires its ability to bind to Homer1, a key postsynaptic scaffolding protein at excitatory synapses, but promotes inhibitory synapse maturation through its ability to bind to Gephyrin, a key scaffolding protein at inhibitory synapses. Finally, SRGAP2 regulates the density of excitatory and inhibitory synapses made onto a pyramidal neuron through its Rac1-GAP activity. Secondly, we and others discovered that SRGAP2 has undergone several partial gene duplications specifically in the human lineage. Only one of these gene duplications, called SRGAP2C (the ancestral copy of the human gene was renamed SRGAP2A) has been fixed in the human population and is expressed in the developing human brain. We discovered that SRGAP2C binds to and inhibits the functions of SRGAP2A during synaptic development. When human-specific SRGAP2C is expressed in mouse cortical pyramidal neurons in vivo, it induces significant delay (neoteny) of synaptic maturation and significant increase in both excitatory and inhibitory synapse density. The present proposal constitutes a comprehensive, multi-disciplinary approach to address some fundamental questions raised by our results from the previous funding period: Is SRGAP2A and its human-specific paralogs only involved in synaptic development or is it also regulating synaptic plasticity? What types of functional properties emerge in mouse cortical circuits following humanization of SRGAP2C expression? What are the consequences of structural changes induced by SRGAP2A and its human- specific paralog SRGAP2C on cortical circuit organization and function as well as behavioral performance? Our aim is to test if human-specific gene duplication of SRGAP2A that led to the emergence of SRGAP2C represented an evolutionary relevant substrate for the emergence of new functional properties in cortical circuits. This project will tackle with unprecedented relevance the relationship between genes, neural circuits and behavior in a framework of human cortical development and evolution.

抽象的在开发过程中，严格调节的机制在兴奋（e）和抑制性（i）对每种神经元细胞类型的突触输入。几种神经发育障碍是被认为是从E/I突触失衡中出现的，包括自闭症谱系障碍（ASD）和精神分裂症。但是，协调兴奋性和抑制性突触发育的机制仍然是理解不佳。我们最近发现SRGAP2是在体内发挥关键作用的突触后蛋白促进兴奋性和抑制性突触的速度，可以成熟并限制两种类型的密度发育中的皮质中的锥体神经元的突触。在上一个资金期间，我们首先做出了在两种兴奋性下剖析SRGAP2功能的分子机制方面的重大进展和抑制突触，发现其促进兴奋性突触成熟的能力需要其能力与HOMER1结合，Homer1是兴奋性突触下突触后脚手架的关键后脚手架蛋白突触通过与gephyrin结合的能力成熟，Gephyrin是一种抑制性突触下的关键支架蛋白。最后，SRGAP2调节兴奋性和抑制性突触的密度通过其Rac1间隙活动。其次，我们和其他人发现SRGAP2特别经历了几种部分基因重复在人类的血统中。这些基因复制中只有一个称为srgap2c（人类的祖先副本基因被更名为SRGAP2A）已固定在人口中，并在发育中表达人脑。我们发现SRGAP2C在突触中结合并抑制SRGAP2A的功能发展。当人体的小鼠皮质金字塔神经元中表达人特异性的srgap2c时，诱导突触成熟的显着延迟（Neoteny），兴奋性和抑制突触密度。本提案构成了一种全面的多学科方法，可以解决一些基本我们上一个融资期的结果提出的问题：是SRGAP2A及其人类特定的仅参与突触发育的旁系同源物还是调节突触可塑性？什么类型 Srgap2c人性化后，小鼠皮质回路中出现的功能特性表达？ SRGAP2A及其人类引起的结构变化的后果是什么皮质电路组织和功能以及行为的特定旁系同源物srgap2c 表现？我们的目的是测试SRGAP2A的人类特异性基因重复是否导致出现 SRGAP2C代表了用于出现新功能特性的进化相关底物皮质电路。该项目将与前所未有的相关性解决基因之间的关系，人类皮质发育和进化框架中的神经回路和行为。