儿童孤独症的神经环路机制研究

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.

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。

孤独症是一种严重的神经发育障碍性疾病，最新的流行病学调查显示孤独症的发病率已达1.14%。遗传学研究显示孤独症相关基因参与神经元的发育过程，神经元的形态建成，突触的稳定和功能发生以及神经环路的形成和稳定等神经生物学过程在孤独症发病中起重要作用。本课题结合课题组前期遗传学研究，分析了多个孤独症相关基因致病的神经生物学机制和神经环路在孤独症发生中的功能影响。其中，我们发现CNTN4可以通过影响APP剪切过程导致突触和神经环路异常，并通过影响wnt/β-catenin途径引起神经前体细胞增殖异常，阐明了CSDE1、POGZ及UBE3A导致神经元发育异常的分子机制，分析确定了CNTN4、CSDE1、UBE3A、PAK2的敲除小鼠行为学表型，发现了视黄酸途径和雷帕霉素对孤独症潜在的治疗作用。同时还对中国人群中孤独症相关基因进行了深入分析，为进一步的开展ASD的神经生物学提供了新的方向。