Serpina3n介导星形胶质细胞GPR30调控学习记忆的机制研究

雌激素替代治疗能够明显改善更年期女性认知功能，但肿瘤风险限制其临床应用，因此寻找雌激素替代治疗新靶点具有重要意义。近年来发现自然衰老或卵巢摘除可引起小鼠中枢星形胶质细胞活化为A1表型，引起学习记忆损害；Serpina3n是形成A1表型的关键分子。我们前期研究发现雌激素膜受体GPR30激动剂G1可改善去势小鼠学习记忆，并能够抑制星形胶质细胞活化，其作用与下调海马脑区Serpina3n表达密切相关。利用星形胶质细胞特异性GPR30基因敲除小鼠，发现小鼠学习记忆减退、突触发育和LTP诱导障碍，提示星形胶质细胞GPR30可能调控突触可塑性参与学习记忆。本项目拟采用分子生物学、形态学、电生理学和行为学等手段深入探究星形胶质细胞GPR30通过下调Serpina3n信号通路抑制星形胶质细胞活化，从而调控突触可塑性参与学习记忆的分子机制，为发掘新的药物治疗靶点奠定基础。

Estrogen replacement therapy significantly improves the cognitive function of menopausal women, but the cancer risk limits its clinical application. Therefore, it is important to find a new drug target of estrogen replacement therapy. In recent years, it has been found that aging or ovariectomy (OVX) can activate astrocytes to A1 phenotype and then induce learning and memory impairment in mice. Serpina3n is a key molecule to form A1 astrocytes. Our previous study found that estrogen membrane receptor GPR30 agonist G1 could improve the learning and memory and inhibit the activation of astrocytes in OVX mice. The effect of G1 was closely related to the downregulation of Serpina3n in the hippocampus. Using astrocytic-GPR30 knockout (KO) transgenic mice, we found that GPR30 deletion in astrocytes caused the deficit of learning and memory, decreased the number of synapsis, and led to LTP-inducing disorder in mice, suggesting that astrocytic GPR30 may modulate learning and memory through regulating synaptic plasticity. In this project, molecular biology, morphology, electrophysiology and behavioral tests are employed to explore the molecular mechanism that GPR30 inhibits astrocyte activation by down-regulating Serpina3n signaling pathway and modulates synaptic plasticity in learning and memory. Our project establishes the research foundation for exploring potential drug target of learning and memory disorders.