TrkB激动剂7,8-dihydroxyflavone对脆性X综合征突触可塑和学习记忆的影响及机制

项目名称： TrkB激动剂7,8-dihydroxyflavone对脆性X综合征突触可塑和学习记忆的影响及机制

项目编号： No.31271199

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 曾燕

作者单位： 武汉科技大学

项目金额： 87万元

中文摘要： Fmr1基因异常导致突触发育和可塑功能障碍是脆性 X综合征智力低下的核心机制，目前该病无药可治。7,8-dihydroxyflavone（7,8-DHF）是最近发现的首个小分子选择性TrkB受体激动剂。我们报道了7,8-DHF重塑树突棘、增强突触可塑性、改善老年及阿尔茨海默病模型学习记忆（图1-3）；最近又发现7,8-DHF增强Fmr1基因敲除小鼠海马区CaMKII和突触蛋白synapsins的磷酸化表达（图4）。我们推测7,8-DHF很可能通过激活TrkB及其下游信号通路改善脆性 X综合征的突触可塑和学习记忆功能。本项目拟采用多种行为、电生理、组织、蛋白质技术，探讨7,8-DHF对Fmr1基因敲除小鼠学习记忆、焦虑反应、突触结构和功能的影响；调查TrkB依赖的突触可塑相关蛋白激活。以期验证7,8-DHF在脆性X综合征动物模型的治疗作用，从分子层面阐明机制，为探索治疗此病的药物提供科学数据

中文关键词： 7; 8-Dihydroxyflavone；TrkB；脆性X综合征；学习记忆；树突棘

英文摘要： Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no current cure for the syndrome. 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a BDNF mimetics to selectively activate tyrosine kinase B receptor (TrkB) with high affinity. We have demonstrated previously that 7,8-DHF in vivo improves aging- and Alzheimer's Disease-associated memory impairments by activating several synaptic plasticity-related signaling proteins, improving synapogenesis and synaptic plasticity. Interestingly, we recently found that chronic 7,8-DHF treatment increases the activation of phosphorylated synapsin I and CaMKII in the hippocampus of Fmr1 gene knockout mice. Thus, correlations between the effect of 7,8-DHF on synapses and the mechanisms underlying the FXS suggest that the 7,8-DHF, via TrkB signaling pathway, may be a potential therapeutic target in FXS-related pathologies. Therefore, in current proposed project, we intend to confirm the rescue effect of 7,8-DHF on Fmr1 gene knockout mice and clarify the mechanisms. We will use miutiple behavioral tests, a variety of electrophysiological recordings, and protein and molecular techniques to assess learning and memory, anxiety, as well as synapogenesis, synaptic plasticity, and the activation of synaptic plasticity- and memor

英文关键词： 7; 8-Dihydroxyflavone；TrkB；fragile X syndrome；learning and memory；Dendritic spine