Role of FMRP in Synaptic Function and Plasticity

FMRP 在突触功能和可塑性中的作用

• 批准号: 6994867
• 负责人: BRAD E PFEIFFER
• 金额: $ 2.7万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6994867
• 关键词: AMPA receptors; RNA binding protein; fragile X syndromes; gene expression; gene mutation; genetically modified animals; laboratory mouse; laboratory rat; neural plasticity; predoctoral investigator; protein structure function; protein transport; receptor mediated endocytosis; synapses; tissue /cell culture

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.

描述（由申请人提供）：脆性X综合征（FXS）是遗传性智力低下的最常见形式，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，在器官型海马切片培养（OHSCs）中瞬时改变FMRP表达水平后，对突触功能进行电生理测量；2) FMRP过表达小鼠和OHSCs中瞬时过表达FMRP和FMRP突变体突触可塑性的电生理分析；3) FMRP过表达小鼠和FMRP敲除小鼠以及OHSCs中谷氨酸受体表达和转运的生化分析。这项研究将对FMRP在突触中的作用提供实质性的见解，并可能为FXS治疗的产生提供动力。