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

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 memory-related proteins in the prefrontal cortex, hippocampus, and amygdala. If these questions have been satisfactorily addressed, it will be an important step on the road of developing a new drug for treating FXS.

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

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。7,8-dihydroxyflavone（7,8-DHF）是首个小分子选择性TrkB 受体激动剂。通过完成本项目，我们发现7,8-DHF 重塑树突棘、增强突触可塑性，改善Fmr1 基因敲除小鼠和阿尔茨海默病（AD）模型学习记忆功能。机制分析表明7,8-DHF 通过激活TrkB及其下游信号通路增强海马区和杏仁核CaMKII，ERK1/2，AMPAR等多个突触功能相关蛋白的磷酸化表达。以上研究结果证明了TrkB激动剂 7, 8-DHF改善脆性 X综合征突触可塑和学习记忆，本研究为治疗神经发育疾病提供了一个新的靶点。. 本项目完成的主要内容：1）调查7,8-DHF对Fmr1基因敲除小鼠空间记忆、恐惧记忆、及焦虑的改善作用，发现7,8-DHF 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，此结果已经正式发表，（ Neuropharmacology. 2015; 89: 43-53.）；2）调查7,8-DHF对AD模型Tg2576小鼠突触发育和学习记忆的影响，发现7,8-DHF 重塑树突棘、增强突触可塑性、改善老年及AD模型的学习记忆，此结果已经正式发表（ J Neurochem. 2016;136 (3):620-36.）；3）,8-DHF 通过激活TrkB及其下游信号通路的分子机制和作用靶点，此结果已经正式发表，（CNS Neurol Disord Drug Targets. 2013, 12(7):809-19.）。. 通过完成此项目，我们共发表了4篇SCI收录论文，其中3篇在A2区；培养了1名硕士研究生，另外还有5名硕士研究生和2名博士研究生正在培养中；参加了国际AAIC会议交流2次，递交会议摘要2篇；本项目还承办了湖北省神经科学理事会1次。