突触后支架蛋白SHANK3过表达导致脆性X综合征突触可塑性异常的机制研究

Fragile X syndrome (FXS) is a common singal gene disorder of autism, mainly manifested as mental retardation, social avoidance, and other language behavior problems. It is very important to explore the pathogenesis of FXS in the search for key regulatory genes in autism. Previously, we found the postsynaptic scaffolding protein SHANK3 expression was increased in the cortex and hippocampus of the Fmr1 KO mice. Moreover, FMRP and Shank3 mRNA were colocalized in the dendrites. With the development of animals, the expression of FMRP decreased while SHANK3 gradually increased. However, it is not clear whether the overexpressed SHANK3 mediated the synaptic developmental disorders, excitatory/inhibitory imbalance and autistic-like behaviors in FXS. The present project combined Fmr1 KO and Shank3 KO mice, in order to study the role of SHANK3 in the increase of dendritic spines, the excessive internalization of AMPAR, the enhancement of mGluR-LTD, and social behavior defects by using electrophysiological, molecular biological, pharmacological, and behavioral methods. This study has implications for understanding the pathogenesis of autism and elucidating the interconnnection between different mutated genes. It will provides new ideas and theoretical basis for drug target discovery and clinical treatment.

脆性X综合征（FXS）是常见的孤独症单基因缺陷疾病模型，主要表现为智力发育迟滞和回避社会互动等语言行为障碍。探索其发病机制对于寻找孤独症中的关键调控基因具有非常重要的意义。我们前期在Fmr1 KO小鼠的皮层和海马中发现突触后支架蛋白SHANK3表达增加，并且FMRP和Shank3 mRNA在树突共定位。随着动物的发育，FMRP表达降低而SHANK3逐渐增加。但是，过表达的SHANK3是否介导了FXS中突触发育障碍、兴奋/抑制传递紊乱和孤独样行为表征还不清楚。本项目拟结合Fmr1 KO和Shank3 KO小鼠，综合利用电生理、分子生物学、药理学和行为学等手段，系统研究SHANK3在树突棘密度增加、AMPAR过度内化、mGluR-LTD增强和社交行为缺陷中的作用。本研究对深入了解孤独症的发病机制，阐明不同突变基因之间的相互联系具有潜在意义，可望为药物靶点发现和临床治疗提供新的思路和理论依据。

脆性X综合征（FXS）是常见的孤独症单基因缺陷疾病模型，主要表现为智力发育迟滞、惊厥发作和回避社会互动等语言行为障碍。探索其发病机制对于寻找孤独症中的关键调控基因具有非常重要的意义。我们的研究结果发现，SHANK3过表达导致了孤独样症状如躁狂行为、社交活动减少和对声音的听觉惊跳增强，这是由特定脑区决定的，并且其行为学表现与FMRP缺失所致症状相一致；孤独症相关蛋白FMRP和SHANK3表达关系呈负相关，在于FMRP可直接结合于Shank3 mRNA的3’非翻译区抑制其翻译，导致表达水平降低；Fmr1 KO小鼠中mGluR5过度激活引起Caveolin-1表达升高，介导GluR2过度内化和mGluR-LTD异常增强；由于FMRP蛋白缺失导致SHANK3表达增多，通过偶联mGluR1/5下游激活的Caveolin1，引起AMPAR过度内化，最终FXS动物出现惊厥发作和学习记忆障碍。本研究对深入了解孤独症的发病机制为药物靶点发现和临床治疗提供新的思路和理论依据。