Study of Fragile X Mental Retardation Protein in Synaptic Function and Plasticity

描述（由申请人提供）：脆性X综合征（FXS）是最常见的遗传性精神发育迟滞形式，由脆性X精神发育迟滞基因（FMR 1）的功能缺失突变引起。患有FXS以及其他形式的精神发育迟滞的患者具有过量的树突棘以及较长的棘，这表明异常的突触后功能、发育或可塑性导致这种疾病的认知缺陷。脆性X智力迟钝蛋白（FMRP）是FMR1的蛋白质产物，是一种RNA结合蛋白，被认为调节树突和树突棘中蛋白质的翻译。这种局部或突触蛋白质合成调节成熟动物的突触发育和长期可塑性。因此，FMRP最有可能通过突触蛋白的翻译调节来介导其神经元效应。与这一想法一致，我们和其他人已经发现FMRP调节青春期神经元的突触修剪以及代谢型谷氨酸受体（mGluRs）的长期突触抑制。FMRP究竟如何调节突触发育和可塑性尚不清楚。这些影响是否是由于树突状合成的蛋白质的翻译调控或这种蛋白质的身份也是未知的。在这里，我们建议检查FMRP调节突触发育和mGluR依赖性突触可塑性的细胞机制。我们还将研究FMRP如何调节树突中蛋白质的合成，并测试2种候选蛋白在FMRP介导的突触修剪和mGluR诱导的突触抑制中的作用。开发和测试治疗FXS和自闭症的新治疗策略，如mGluR拮抗剂，是NIH的使命。我们的研究结果有望提供FMRP如何，或其缺乏，调节突触成熟和mGluR依赖的突触可塑性在成人的知识。这些结果将有助于确定精神发育迟滞和相关疾病（如自闭症）的神经生物学基础，并测试mGluR拮抗剂是否是FXS的合适治疗策略。该补助金的具体目标是：1.检查突触发育和消除的FMRP调节。2确定FMRP磷酸化在调节突触数量和mGluR诱导的树突状蛋白合成中的作用。确定FMRP是否是LTD的急性调节剂，4.脆性X综合征（Fragile X Syndrome，FXS）是最常见的遗传性精神发育迟滞，也是自闭症的主要原因之一。FXS是由脆性X智力迟钝蛋白（FMRP）的功能缺失突变引起的。我们的研究将确定FMRP如何在大脑中正常工作，以及如何以及为什么没有FMRP的大脑功能不同。这项工作预计将提供重要的知识，发展治疗精神发育迟滞和自闭症。

DESCRIPTION (provided by applicant): Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and is caused by loss of function mutations in the Fragile X Mental Retardation gene (FMR1). Patients with FXS as well as other forms of mental retardation have an excess of dendritic spines as well as longer spines, suggesting that abnormal postsynaptic function, development or plasticity contributes to the cognitive deficits of this disease. Fragile X Mental Retardation Protein (FMRP), the protein product of FMR1, is an RNA binding protein and is thought to regulate translation of proteins in dendrites and dendritic spines. Such local or synaptic protein synthesis regulates both synapse development and long-term plasticity in mature animals. Therefore, FMRP most likely mediates its neuronal effects through translational regulation of synaptic proteins. Consistent with this idea, we and others have discovered that FMRP regulates synapse pruning in adolescent neurons as well as long-term synaptic depression by metabotropic glutamate receptors (mGluRs). Exactly how FMRP regulates synapse development and plasticity is unknown. Whether these effects are due to translational regulation of dendritically synthesized proteins or the identity of such proteins is also unknown. Here we propose to examine the cellular mechanisms by which FMRP regulates synapse development and mGluR- dependent synaptic plasticity. We will also examine how FMRP regulates the synthesis of proteins in dendrites and test 2 candidate proteins for their role in FMRP mediated synaptic pruning and mGluR-induced synaptic depression. Developing and testing new therapeutic strategies for treatment of FXS and autism, such as mGluR antagonists, is a mission of the NIH. Our results are expected to provide knowledge of how FMRP, or its absence, regulates synapse maturation and mGluR-dependent synaptic plasticity in the adult. These results will help to determine the neurobiological basis of mental retardation and related disorders such as autism as well as test if mGluR antagonists are a suitable therapeutic strategy for FXS. The specific aims of the grant are: 1. Examine FMRP regulation of synapse development and elimination. 2 Determine the role of FMRP phosphorylation in regulation of synapse number and mGluR-induced dendritic protein synthesis, 3. Determine if FMRP is an acute regulator of LTD, 4. Test candidate proteins for their involvement in LTD and FMRP induced synapse elimination.Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and a leading cause of autism. FXS is caused by loss of function mutations in the Fragile X Mental Retardation protein (FMRP). Our research will determine how FMRP normally works in the brain as well as how and why the brain functions differently without FMRP. This work is expected to provide important knowledge to development therapies for mental retardation and autism.