儿童孤独症的神经环路机制研究

项目名称： 儿童孤独症的神经环路机制研究

项目编号： No.81330027

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 夏昆

作者单位： 中南大学

项目金额： 290万元

中文摘要： 孤独症是一种严重的儿童神经发育性疾病。最新流行病学调查发现孤独症的发病率已达1.14%。遗传学研究发现一些比较确定的孤独症易感基因，这些基因主要参与神经发育过程，如突触发生和突触可塑性等。已有研究大多是从单个基因出发研究他们的功能及其参与的神经生物学机制，从系统水平研究孤独症神经环路还没有太大进展。本课题将以前期的孤独症易感基因定位克隆和功能机制研究为基础，以CNTN4,CNTNAP2,AMPD1三个基因敲除小鼠为动物模型，利用最新的光遗传学等技术阐明孤独症相关的脑区和神经环路。利用全基因组mRNA表达分析找出与孤独症表型相关显著表达差异基因，并选取关键基因在新生鼠中利用慢病毒载体介导的siRNA干扰技术研究孤独症相关神经环路的发生机制，同时研究表达显著下调关键基因的修复是否能够rescue敲除小鼠的孤独症相关表型，从而验证前期结果。本研究将对阐明孤独症的分子致病机制具有重要作用。

中文关键词： 孤独症;神经环路;CNTN4;CNTNAP2;AMPD1

英文摘要： Autism is a severe neurodevelopmental disorder with high clinical and geneticheterogeneity.According to the epidemiologicalstudy, the prevalence of autism has reached 1.14% in 2012.Autism related genes, which involve in the process of neural developmentsincluding synaptogenesis and synaptic plasticity,have been discovered in recent autism studies.Previous studies mainly focused on single genes and their functions and how they function in neurobiological mechanisms.However, there is no advanced study on the neural circuit mechanism of autism.This proposal, based on previous risk genes cloning and functional studies, aims to clarify autism associated brain areas and neural circuits by using new strategies like optogenetic technologiesbased on three knock-out mouse models we have obtained.We will also perform whole genome mRNA sequencing to identify expression pattern and expression differential genesbetween WT and KO mice.Theses identified gene or pathway will be selected to study how they contribute in neural circuit mechanism in drosophila knock-in or knock-out model. Finally, we will select some key low expressed genes in KO mice and knock them into the KO mice to determine whether they can rescue the phenotype(s) of KO mice. This proposal is important for clarifying the molecularpathogenicmechanism of autism.

英文关键词： autism;neural circuit;CNTN4;CNTNAP2;AMPD1