脆性X综合症模型小鼠雌激素ER-β调节突触可塑性异常的机制研究

项目名称： 脆性X综合症模型小鼠雌激素ER-β调节突触可塑性异常的机制研究

项目编号： No.31300877

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 郭艳艳

作者单位： 中国人民解放军第四军医大学

项目金额： 24万元

中文摘要： 脆性X综合症为临床常见的遗传性智力低下症,但其发生机制一直不清楚。雌激素受体(ERα和ERβ)在脑内广泛分布，参与多种中枢生理功能，如学习与记忆、情感和认知等。我们前期研究发现激动雌激素受体ERβ显著促进前扣带回皮层LTP，但在脆性X综合症模型小鼠ERβ促进诱导LTP作用消失，提示ERβ受体功能的异常可能参与了脆性X综合症动物学习与认知能力障碍。然而ERβ受体突触可塑性调节异常的分子机制目前尚未见报道。本项目以FMR1 基因敲除小鼠为研究模型，首次从ERβ受体调节可塑性异常入手，利用电生理、免疫组织化学、药理学和行为学等手段，探索ERβ受体与脆性X综合症病理机制的关系，以期阐明脆性X综合症ERβ受体突触可塑性调节异常的分子机制，进一步认识脆性X综合症的病理机制，发掘潜在的药物治疗新靶点，为临床治疗提供新的思路和理论依据。

中文关键词： 脆性X综合征；突触可塑性；雌激素；小窝蛋白；学习与记忆

英文摘要： Fragile X syndrome is the common clinical inherited mental retardation disorders. Estrogen receptor (ERα and ERβ) are widely distributed in the brain, involved in a variety of central physiological and pathological functions, such as learning and memory, emotion and cognition. Our previous study found that activation of ERβ significantly promoted the LTP induction in anterior cingulate cortex and activation of ERα had no significant effect on the LTP induction. However, the LTP facilitation of LTP by ERβ was disappeared in the mouse model of Fragile X syndrome, suggesting the dysfunction of the ERβ receptor may be involved in the learning and cognitive disabilities of Fragile X syndrome animal. However, the molecular mechanism underlying the dysregulation in synaptic plasticity by ERβ receptors has not been reported. This project aims to clarify the molecular mechanisms of ERβ receptor in synaptic plasticity in Fragile X syndrome by using the FMR1 gene knockout mice and electrophysiological, immunohistochemical, pharmacological and behavioral methods. It is the first time to explore the significance of ERβ receptor in the Fragile X syndrome. This project will help to further understand the pathological mechanism of the Fragile X syndrome, and identify potential new target for drug therapy, and provide new ideas

英文关键词： Fragile X syndrome；Synaptic plasticity；Estrogen； caveolin；learning and memory