膜-细胞骨架连接蛋白Ezrin介导星形胶质细胞精细分支形态异常在认知功能障碍中的作用及机制研究

突触结构和功能障碍是多种认知功能障碍性疾病的早期病理改变，且是与临床症状最相关的病理表型，但其机制仍需进一步阐明。星形胶质细胞精细分支可包绕突触前和突触后结构，形成“三突触”结构，参与神经环路和行为调控。申请人已发表研究发现膜-细胞骨架连接蛋白Ezrin是调控星形胶质细胞精细分支形成的关键蛋白。申请人预实验结果提示下调成年小鼠海马区星形胶质细胞Ezrin导致精细分支萎缩、突触功能和认知功能障碍。基于此，申请人提出假说：海马区星形胶质细胞Ezrin下调引起的精细分支萎缩将导致“三突触”结构障碍、星形胶质细胞与神经元交互障碍，从而导致突触功能和认知功能障碍；上调星形胶质细胞Ezrin可改善认知功能障碍。本项目将使用基因工具、电镜、电生理、行为学、转录组学等手段，证实Ezrin下调引起的星形胶质细胞精细分支萎缩是认知功能障碍的重要发病机制，为早期防治认知功能障碍提供新靶点。

Altered synaptic structure and function are common pathological features of many cognitive disorders. These pathological phenotypes correlate best with clinical symptoms, however, the mechanisms of synaptic impairment remain incompletely understood. Astrocyte fine processes closely enwrap the pre- and postsynaptic compartments, forming “tripartite synapses”, and play vital roles in neural circuit and behaviors. Our published study demonstrated that astrocytic actin-binding protein Ezrin is a key structural determinant of astrocyte fine processes. Our preliminary data here showed that the down-regulation of astrocytic Ezrin in hippocampus led to synapse dysfunctions and cognitive impairments in adult mice. Based on these observations, we hypothesize that down-regulated expression of hippocampal astrocytic Ezrin leads to atrophy of astrocyte fine processes, disrupts “tripartite synapses” and impairs astrocyte-neuron interaction, which results in synaptic dysfunction and cognitive impairment, and up-regulation of astrocytic Ezrin could improve cognitive impairment. By using genetic tools, electron microscopy, electrophysiology, neurobehavioral assessments, transcriptomics and other techniques, we would demonstrate that astrocyte fine processes atrophy due to down-regulation of astrocytic Ezrin is an important pathogenesis of cognitive impairment, which represents a novel target for the prevention or treatment for cognitive impairment.