小胶质细胞I型干扰素信号异常抑制海马神经发生致自闭症发生的作用及机制研究

海马齿回神经发生缺陷是自闭症病理发生的关键结构与功能基础，小胶质细胞功能异常引起海马齿回神经发生缺陷。我们前期研究发现自闭症模型BTBR小鼠海马齿回中维持小胶质细胞I型干扰素(IFN-I) 信号稳态的小胶质细胞亚群显著减少，并导致海马齿回神经发生抑制，提示BTBR小鼠海马齿回中小胶质细胞特征亚群分布改变及其基因表达谱的变化，可能导致齿回神经干细胞的微环境出现持续升高的IFN-I，从而抑制海马神经发生和社交环路的形成。本课题将采用BTBR小鼠结合基因转染、小胶质细胞与放射状胶质细胞（RGC）共培养、流式细胞分选与检测、膜片钳记录等技术，旨在研究BTBR小鼠海马齿回发生关键期，特定小胶质细胞亚群内USP18下调引起IFN-I信号通路持续激活并释放TNF，下调RGC中转录因子TCF4抑制齿回神经发生的关键作用途径与分子机制。研究结果可望从全新的角度阐明自闭症的机制，为自闭症的治疗提供新的线索。

Deficit in the hippocampal neurogenesis is considered to be a factor related to pathogenesis of autism. Microglia dysfunction is involved in the autism pathogenesis by the inhibited neurogenesis of hippocampal dentate gyrus (DG). Our previous study revealed that the microglia cluster maintaining the stable state of type I interferon (IFN-I) signal in the DG of autistic BTBR mice were significantly reduced, which led to the inhibition of DG neurogenesis. It is suggested that the changes in the distribution of microglia clusters and their gene expression profiles in the hippocampus DG of BTBR mice may lead to the continuous increase of IFN-I signal in the microenvironment of neural stem cells in the DG, thus inhibiting the hippocampal neurogenesis and the formation social circuit. In the present study, we will use BTBR mice combined with gene transfection, microglia and radial glia co-culture, flow cytometry separation and detection, patch clamp recording and other technologies to explore the underlying mechanism that the down-regulation of USP18 in a specific microglia cluster, could cause the continuous activation of IFN-I signal pathway and release of TNF, and inhibit DG neurogenesis via inhibition of TCF4 expression in the RGC. These results are expected to clarify the pathogenesis of autism from a new perspective and provide new clues for the prevention and treatment of autism.