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（申请人提供）：脆性X染色体智力低下综合征是人类智力低下最常见的遗传形式之一。脆性X综合征的分子遗传学基础已经确定;脆性X智力低下-1基因（FMR 1）的突变导致蛋白质产物脆性X智力低下蛋白（FMRP）的丢失。尽管我们对脆性X综合征有遗传学上的了解，但FMRP的生物学功能仍然未知。现在可以使用Fmrl-KO小鼠研究FMRP的作用，Fmrl-KO小鼠是脆性X综合征的转基因模型，其中FMRP已被基因敲除。我们实验室最近的工作使用这些小鼠来确定FMRP在调节大脑中活性依赖性突触可塑性中的功能作用; FMR 1-KO小鼠表现出由代谢型谷氨酸受体（mGluR）激活诱导的突触强度的长期抑制（LTD）增加。我们假设缺乏FMRP会增加大脑中mGluR依赖性蛋白质合成和/或长期抑郁（LTD），可能是脆性X智力低下的潜在原因。具体来说，我们的目的是测试的可能性，异常树突棘的形成和脆性X综合征相关的癫痫样活动的易感性增加是一个不适当的mGluR调节的直接后果。通过这种机制的联系，我们希望解释脆性X综合征的形态，生理和行为特征，并制定治疗策略。