孤独症是一种多基因复杂疾病，核心症状为社会交往及交流障碍、认知损害和刻板兴趣行为等脑高级功能障碍，建立基因工程动物模型有助于揭示孤独症的发病机制。既往研究发现孤独症患者存在AUTS2基因的缺失或突变。目前，AUTS2已是孤独症研究领域的国际热点，但Auts2缺陷小鼠是否有孤独症样行为表现以及Auts2对出生后小鼠神经系统发育的影响尚不清楚。课题组前期发现Auts2条件性敲除小鼠出现孤独症样行为以及前额叶皮层、海马齿状回神经发育异常表型。本项目将在系统评价小鼠行为学的基础上，采用免疫组化、子宫内电穿孔和Golgi染色等方法观察神经细胞增殖分化、神经元迁移、树突发育和突触形成等发育事件；利用电生理学记录手段明确神经元的兴奋性、基础突触传递、兴奋性/抑制性平衡和可塑性等特征；进而探索Auts2缺失影响神经发育和神经元活动的分子机理。本项目将为揭示孤独症易感基因AUTS2的致病机制提供重要线索。

Autism is a complex genetic disease and is characterized by advanced brain dysfunction such as social deficit, cognitive impairment and stereotypic interests and behaviors. It is helpful to reveal the pathogenesis of autism by constructing genetically engineered animal models. Deletions or mutations of AUTS2 genomic sequences have been found in autistic patients. So far, AUTS2 has become an international important issue in autism research field, but it is unclear that whether the Auts2 deficient mice have autism-like behaviors or postnatal neural development abnormality. Our previous work indicated Auts2 conditional knockout mice showed autism-like behaviors and neural development deficits in prefrontal cortex and dentate gyrus. Based on systematic assessment of mice behaviors, we will detect neural proliferation, differentiation, migration, dendrite development and synaptic formation by using immunostaining, in utero electroporation and Golgi staining. Taking advantage of electrophysiological recording to study neuronal excitability, basal transmission, excitability/inhibition equilibrium and synaptic plasticity. At last we will explore the related molecular mechanism. This research will provide important clues to reveal the pathogenic mechanism of autistic susceptibility gene AUTS2.