Role of FMRP in Synaptic Function and Plasticity

描述(申请人提供)：脆性X综合征(FXS)是最常见的遗传性智力低下形式，由脆性X智力低下蛋白(FMRP)功能丧失引起。对FXS患者和FXS小鼠模型的研究表明，FMRP对于正常的突触功能和可塑性至关重要。我建议通过三个主要目标来研究FMRP在突触功能中的作用：1)通过使用FMRP突变体和瞬时改变FMRP基因的表达水平，对突触功能进行电生理学检测；2)电生理分析FMRP过表达小鼠和FMRP和FMRP突变体瞬时过表达后OHSCs中的突触可塑性；3)生化分析谷氨酸受体在FMRP高表达和FMRP基因敲除小鼠以及FMRP瞬时表达改变后OHSCs中的表达和转运。这项研究将为FMRP在突触中的作用提供实质性的见解，并可能为FXS的治疗提供动力。

DESCRIPTION (provided by applicant): Fragile X Syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of function of the Fragile X Mental Retardation Protein (FMRP). Studies of FXS patients and mouse models of FXS suggest that FMRP is critical for proper synaptic function and plasticity. I propose to investigate the role of FMRP in synaptic function through three major aims: 1) Electrophysiological measurements of synaptic function following transient alteration of FMRP expression levels in organotypic hippocampal slice cultures (OHSCs) and through the use of FMRP mutants; 2) Electrophysiological analysis of synaptic plasticity in FMRP-overexpressing mice and in OHSCs following transient overexpression of FMRP and FMRP mutants; and 3) Biochemical analysis of glutamate receptor expression and trafficking in FMRP-overexpressing and FMRP-knockout mice and in OHSCs following transient alterations in FMRP expression. This research should give substantial insight into the role of FMRP at the synapse and may provide impetus for the generation of a treatment for FXS.