The Etiology of Fragile X Mental Retardation Syndrome

脆性X智力低下综合症的病因学

• 批准号: 7005689
• 负责人: Gul Dolen
• 金额: $ 4.34万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005689
• 关键词: brain electrical activity; confocal scanning microscopy; dendrites; disease /disorder etiology; electrophysiology; fragile X syndromes; genetically modified animals; glutamate receptor; hippocampus; immunocytochemistry; laboratory mouse; nerve /myelin protein; neural plasticity; neuropharmacology; predoctoral investigator; protein biosynthesis; receptor expression; receptor sensitivity; synapses; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Fragile X mental retardation syndrome is one of the most common heritable forms of mental retardation in humans. The molecular genetic basis of fragile X syndrome has been identified; mutation of the fragile X mental retardation-1 gene(FMR1) leads to a loss of the protein product, the fragile X mental retardation protein (FMRP). Despite our genetic understanding of fragile X syndrome, the biological function of FMRP remains unknown. The role of FMRP can now be studied using the Fmrl-KO mouse, a transgenic model of fragile X syndrome in which FMRP has been genetically knocked out. Recent work in our lab has used these mice to identify a functional role for FMRP in regulating activity-dependent synaptic plasticity in the brain; FMR1-KO mice exhibit increased long-term depression (LTD) of synaptic strength induced by metabotropic glutamate receptor (mGluR) activation. We hypothesize that a lack of FMRP increases mGluR-dependent protein synthesis and/or long-term depression (LTD) in the brain and might be an underlying cause of fragile X mental retardation. Specifically, we aim to test the possibility that the abnormal dendritic spine formation and increased susceptibility to epileptiform activity associated with fragile X syndrome is a direct consequence of inappropriate mGluR regulation. Through this mechanistic link, we hope to account for the morphological, physiological, and behavioral characteristics of fragile X syndrome and to devise strategies for therapeutic treatments.

描述（由申请人提供）：脆弱的X心理迟缓综合征是人类中最常见的遗传性智力低下形式之一。已经确定了脆弱X综合征的分子遗传基础。脆弱的X智力低下1基因（FMR1）的突变导致蛋白质产物的丧失，即脆弱的X智力低下蛋白（FMRP）。尽管我们对脆弱X综合征的遗传理解，但FMRP的生物学功能仍然未知。现在可以使用FMRL-KO小鼠（一种脆弱X综合征的转基因模型，其中FMRP被遗传淘汰的转基因模型，可以研究FMRP的作用。我们实验室中的最新工作使用这些小鼠来确定FMRP在调节大脑中活动依赖性突触可塑性方面的功能作用。 FMR1-KO小鼠表现出增加的长期抑郁症（LTD）的突触强度，由代谢型谷氨酸受体（MGLUR）激活诱导。我们假设缺乏FMRP会增加大脑中MGLUR依赖性的蛋白质合成和/或长期抑郁（LTD），并且可能是造成X智力低下的根本原因。具体而言，我们旨在测试异常的树突状脊柱形成和增加与脆弱X综合征相关的癫痫样活性的敏感性是不适当的MGLUR调节的直接结果。通过这种机械链接，我们希望解释脆弱X综合征的形态，生理和行为特征，并制定治疗疗法的策略。