Dock4作用于海马CA1区调控NMDA受体表达和社交行为的细胞及分子机制研究

社交异常是孤独症谱系障碍(ASD)的核心症状之一。海马是调控社交行为的重要脑区，在ASD人群中多有形态及功能改变，但海马特定亚区参与社交行为的细胞特异性机制不甚明确。申请人前期发现，海马CA1区缺失ASD易感基因Dock4使小鼠丧失社交新奇偏好，NMDA受体表达下调是重要机制。基于此，本项目拟特异敲除背/腹侧CA1中兴奋或抑制性神经元的Dock4，或通过化学遗传学操控敲除鼠中这些神经元的活性，观察社交行为是否改变或逆转。进而运用多种蛋白质合成检测手段，选取前期质谱鉴定的与Dock4结合的候选蛋白，探究Dock4通过mRNA翻译途径调控NMDA受体蛋白表达的细胞特异性分子机制，并阐明该调控与社交行为的关系。本研究旨在明确Dock4调控社交行为所作用的CA1亚区和细胞类型，解析Dock4维持NMDA受体正确表达参与社交行为的细胞及分子机理，为揭示海马受损关联ASD社交障碍的病理机制提供新证据。

Social deficits are among the core symptoms of autism spectrum disorder (ASD). Hippocampus is crucial for regulating social behavior, and structural and functional abnormalities of hippocampus are commonly observed in ASD individuals. However, how subregion- and cell type-specific events in hippocampus participate in social behaviors has remained unclear. Our previous study revealed that deficiency of the ASD candidate gene Dock4 in mouse hippocampal CA1 leads to failure of social novelty preference in the mice. Reduced protein expression and function of NMDA receptor subunits appeared to be the main reason underlying this abnormality. Based on these observations, the current study will begin by specifically deleting Dock4 in either excitatory of inhibitory neurons in the dorsal or ventral CA1 using the Cre-LoxP method by injecting Cre under different promoters in Dock4 floxed mice, and examine the social behaviors of the mice. On the other hand, we will use Chemogenetics to manipulate the activities of different neuron types in dorsal or ventral CA1 in Dock4 knockout mice, and examine whether the failed social behaviors could be rescued. In the second part, we will use a series of de novo protein synthesis measurement techniques to examine whether Dock4 regulates the translation of the mRNAs of NMDA receptor subunits into proteins, and whether this regulation is hippocampal subregion and cell type-specific. By studying the candidate interacting partner of Dock4, we will further interrogate the molecular mechanism that governs the regulation of de novo protein synthesis of NMDA receptor and thus the correct social behaviors. This study aims to uncover the hippocampal subregion and cell type in which Dock4 acts to regulate NMDA receptor expression and social behaviors, and elucidate the underlying molecular mechanism. Findings from this study will greatly contribute to the understanding of hippocampus-dependent pathophysiology of ASD.