The Etiology of Fragile X Mental Retardation Syndrome

描述（由申请人提供）：脆性X智力发育迟滞综合征是人类最常见的遗传性智力发育迟滞形式之一。脆性X综合征的分子遗传基础已经确定；脆性X智力发育迟缓-1基因（FMR1）的突变导致蛋白质产物脆性X智力发育迟缓蛋白（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。FMRP的作用现在可以用Fmrl-KO小鼠来研究，FMRP是一种脆性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利用这些小鼠来确定FMRP在调节大脑活动依赖性突触可塑性中的功能作用；FMR1-KO小鼠表现出代谢性谷氨酸受体（mGluR）激活引起的突触强度长期抑制（LTD）增加。我们假设缺乏FMRP会增加大脑中mglur依赖性蛋白合成和/或长期抑郁（LTD），这可能是脆性X智力迟钝的潜在原因。具体来说，我们的目的是测试与脆性X综合征相关的异常树突棘形成和对癫痫样活动易感性增加的可能性是不适当的mGluR调节的直接后果。通过这种机制联系，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。

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.