CNTN6通过调控抑制性中间神经元发育参与孤独症谱系障碍发病的机制研究

Autism spectrum disorder is a spectrum of autism-related neurodevelopment disorders. About 1 in 68 children were diagnosed with ASD in the United States. ASD still have no cure and the treatment is expensive, giving rise to weighty economy burden. For now, etiology and pathogenesis of ASD are still elusive. Previous human genetic studies have revealed CNTN6 as a new candidate gene of ASD; however, the precise mechanisms that CNTN6 involved in etiology of ASD need further investigation. We found that male CNTN6-/- mice show autistic-like behaviors such as impaired social interaction, impaired communication, lower interest in novel objective recognition, mild impaired spatial memory and motor incoordination. Moreover, the number of Calb1-positive GABAergic neurons in cerebral cortex of male CNTN6-/- mice is significantly decreased. We also find the interaction between CNTN6 and Slit2. CNTN6 regulates cortical neurites outgrowth and cancels the repulsive action of Slit2 on LGE GABAergic neurons migration, indicating the important regulating roles of CNTN6-Slit2 interaction in inhibitory neural network development. In this project, we aim to reveal the precise functions of CNTN6-Slit2 interaction in GABAergic neuron development and migration, excitatory-inhibitory network formation and animal behaviors, and clarify its molecular and psychology mechanism. Completion of this project will fill the gap between genetic study and functional study of CNTN6 in pathogenesis of ASD. CNTN6-Knockout mice can also be used as new model of ASD, helping to elucidate the etiology of ASD.

孤独症谱系障碍（Autism Spectrum Disorder, ASD）是一类严重的神经发育障碍。该类疾病患病率高，尚无治愈方法，其病因及发病机制尚未完全阐明。CNTN6是ASD的易感基因之一，但其参与ASD发病的机制尚不清楚。申请人前期研究发现CNTN6-/-的雄性小鼠出现ASD样行为，其大脑皮层Calbindin1阳性的GABAergic神经元数量显著降低。CNTN6与Slit2相互作用，共同参与调控皮层神经元突起的外向生长及外侧神经节隆起中GABAergic神经元的迁移。本课题将运用CNTN6-/-模型，从多层次研究CNTN6与Slit2相互作用及相关信号通路在GABAergic神经元发育、兴奋-抑制性神经网络的形成和平衡以及动物行为中作用，阐明CNTN6参与ASD发病的分子和生理机制。该研究将完善CNTN6的功能学研究，提供新的ASD模式动物，加深我们对ASD发病机制的认知。

孤独症谱系障碍（Autism Spectrum Disorder, ASD）是一类严重的神经发育障碍。该类疾病患病率高，尚无治愈方法，其病因及发病机制尚未完全阐明。CNTN6是ASD的易感基因之一，但其参与ASD发病的机制尚不清楚。本研究发现CNTN6与神经导向因子Slit2存在直接相互作用，可逆转Slit2对GABAergic神经元突起的外向生长和迁移的抑制作用。CNTN6敲除小鼠皮层中的Calbindin阳性的GABAergic神经元数量显著减少。雄性CNTN6敲除小鼠表现出社交障碍和刻板行为等ASD核心症状。此外，CNTN6敲除雄鼠存在同物种间识别和性行为异常，这可能与副嗅球中僧帽细胞和颗粒细胞间突触异常以及副嗅球系统环路的活性异常密切相关。该研究部分阐明了CNTN6参与ASD发病的分子和生理机制。完善了CNTN6的功能学研究，提供新的ASD模式动物，加深我们对ASD发病机制的认知。