脆性x综合征小鼠前额叶皮层突触传递长时程增强的网络特性研究

Fragile X syndrome (FXS) is the most common inherited cause of autism and disability in learning and recognition, and it typically results from transcriptional silencing of fmr1 and loss of the encoded fragile X mental retardation protein (FMRP). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation. Recent studies on the function of FMRP and the signaling pathways confused on the hippocampus and little is known about the pathological changes in the cortex, especially the prefrontal cortex, a well-known area for learning, memory and emotional regulation. In the present study, by combing a 64 channels array recording system with Neural Network Dynamics and Cluster Analysis, we studied the network properties of the late phase long-term synaptic potentiation (L-LTP), a transcription and translation-related cellular model for learning/recognition and emotion regulation, in the PFC of fmr1 knockout mice. Furthermore, immuno-electron microscopic, biochemical, whole cell patch recording and behavioral methods were explored to study the synapse ultrastructure and dynamic of the postsynaptic NMDA, AMPA receptor in the PFC, as well as the involvement of mGluR5 and TrkB downstream signaling pathways in the regulation of the deficiency caused by loss of FMRP . Our proposed study will be helpful for revealing the mechanism of FXS and providing potential basic and clinical strategies for FXS treatment.

脆性X 综合征(FXS)为不完全显性X连锁遗传病, 主要表现为认知障碍和孤独症样行为。发病的主要原因是脆性X 智力低下基因( fmr1)异常和其编码产物脆性x智力低下蛋白(FMRP)的缺失。目前研究集中于FXS的海马机制，对皮层尤其是前额叶皮层（PFC）的研究非常匮乏。本研究以fmr1基因敲除的小鼠为实验对象，通过64通道/位点的场电位记录，结合神经动力学和聚类分析的方法，探索fmr1野生型和基因敲除动物PFC内不同记录位点的晚期突触传递长时程增强（L-LTP）的特性，并深入分析不同记录位点之间的相互联系等网络特征。同时，综合利用免疫电镜、分子生物学、全细胞记录和行为药理学等方法，对FXS小鼠PFC内突触超微结构、突触后谷氨酸受体的位置、功能等特性以及mGluR5和TrkB受体相关信号传导通路的作用机制进行研究。以期探索FXS的发病机制和关键影响因素，为Fxs的临床治疗提供实验依据和指导。

脆性X 综合征(FXS)为不完全显性X连锁遗传病, 主要表现为认知障碍和孤独症样行为。发病的主要原因是脆性X 智力低下基因( fmr1)异常和其编码产物脆性x智力低下蛋白(FMRP)的缺失。目前研究集中于FXS的海马机制，对皮层尤其是前额叶皮层（PFC）的研究非常匮乏。本研究以fmr1基因敲除的小鼠为实验对象，主要通过64通道/位点的场电位记录，结合神经动力学和聚类分析的方法，探索fmr1野生型和基因敲除动物PFC内不同记录位点的晚期突触传递长时程增强（L-LTP）的特性，并深入分析不同记录位点之间的相互联系等网络特征。同时，综合利用免疫电镜、分子生物学、全细胞记录和行为药理学等方法，对FXS小鼠PFC内突触超微结构、突触后谷氨酸受体的位置、功能等特性以及细胞内相关信号传导通路的作用机制进行了研究。研究为探索FXS的发病机制和关键影响因素，Fxs的临床治疗提供了实验依据和指导。