认知功能障碍是糖尿病中枢神经系统并发症的主要临床表现，而海马组织突触可塑性改变是糖尿病认知功能障碍发病的重要环节，但其发生机制未明。我们的前期研究发现，核受体共激活因子3（NCOA3）在糖尿病小鼠的海马组织和体外高糖刺激的海马神经元中表达降低，并伴有突触可塑性标志分子PSD-95及突触小泡蛋白(SYP)表达的下降；而过表达NCOA3可逆转高糖对PSD-95和SYP的影响，提示NCOA3是调控高糖环境所致海马神经元突触可塑性改变的关键分子。进一步研究发现，Ago2可能是介导NCOA3调控突触可塑性的下游因子。在前期研究基础上，本项目拟以神经元特异性过表达NCOA3的小鼠和体外培养的海马神经元为研究对象，探讨NCOA3在糖尿病认知功能障碍发病机理中的作用，并阐明NCOA3通过Ago2调控突触可塑性的分子机制，期望深化目前对糖尿病认知功能障碍发病机理的认识，并为其防治提供新思路。

Diabetes mellitus is an important chronic disease which seriously endangers human health. It can cause serious damage in central nervous system which manifests cognitive impairment in different degrees. Studies have shown that changes of hippocampal synaptic plasticity play important role in cognitive dysfunction in diabetes, but the mechanism is not clear. Our previous studies showed that the expression of nuclear receptor co-activator 3 (NCOA3) decreased in the hippocampus of STZ-induced diabetic mice, while the expression of NCOA3 was down-regulated in hippocampal neurons cultured in vitro stimulated by high glucose, followed by the decreased expression of PSD-95 and synaptophysin （SYP）. Upregulation of NCOA3 expression can reverse the expression of PSD-95 and SYP induced by high glucose. These results indicated that NCOA3 is the key molecular in mediating changes of synaptic plasticity and playing a critical role in diabetic cognitive impairment. Our further studies suggest that Ago2 is central to the function of NCOA3 in diabetes. Therefore, on the basis of our previous experiments we are going to investigate the significance of NCOA3 in hippocampal synaptic plasticity and the pathogenesis of cognitive impairment in diabetic patients and the effect of Ago2 in above processes in cultured neurons and neuronal specific expression of NCOA3 mice. By this investigation, we expect to clarify and elucidate the role and the mechanisms of NCOA3 in the early stage of cognitive impairment in diabetic patients. This study will shed light on the exploration of its effective therapies.