The Etiology of Fragile X Mental Retardation Syndrome

描述(申请人提供)：脆性X智力低下综合征是人类最常见的遗传性智力低下形式之一。脆性X综合征的分子遗传学基础已被证实，脆性X智力低下-1基因(FMR1)突变导致脆性X智力低下蛋白(FMRP)的蛋白产物丢失。尽管我们对脆性X综合征有遗传学上的了解，但FMRP的生物学功能仍不清楚。FMRP的作用现在可以用Fmrl-KO小鼠来研究，Fmrl-KO小鼠是一种脆性X综合征的转基因模型，在这种模型中，FMRP已经被基因敲除。我们实验室最近的工作是利用这些小鼠来确定FMRP在调节大脑中活性依赖的突触可塑性中的功能作用；FMR1-KO小鼠表现出由代谢性谷氨酸受体(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会增加大脑中依赖mGluR的蛋白质合成和/或长期抑郁(LTD)，可能是脆性X智力低下的潜在原因。具体地说，我们的目标是测试与脆性X综合征相关的异常树突棘形成和癫痫样活动易感性增加是否是mGluR调节不当的直接后果。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，并设计治疗策略。

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.