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）是最常见的遗传形式的智力低下，是由脆性X智力低下基因（FMR1）的功能突变丧失引起的。FXS患者以及其他形式的智力发育迟滞患者的树突棘过多，棘较长，提示突触后功能、发育或可塑性异常导致了该疾病的认知缺陷。脆性X智力迟钝蛋白（FMRP）是FMR1的蛋白产物，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的合成调节着成熟动物突触的发育和长期可塑性。因此，FMRP很可能是通过对突触蛋白的翻译调节来调节其神经元效应的。与这一观点一致，我们和其他人发现FMRP调节青春期神经元的突触修剪以及代谢性谷氨酸受体（mGluRs）的长期突触抑制。FMRP究竟如何调节突触的发育和可塑性尚不清楚。这些影响是由于树突合成蛋白的翻译调控还是这些蛋白的特性还不清楚。在这里，我们建议研究FMRP调节突触发育和mGluR依赖的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种候选蛋白质在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，是美国国立卫生研究院的一项使命。我们的研究结果有望提供关于FMRP或其缺失如何调节成人突触成熟和mglur依赖的突触可塑性的知识。这些结果将有助于确定智力迟钝和相关疾病（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。赠款的具体目的是：1。检查FMRP对突触发育和消除的调节。2 .确定FMRP磷酸化在调控突触数量和mglur诱导的树突蛋白合成中的作用；3 .确定FMRP是否是LTD的急性调节器。测试候选蛋白参与LTD和FMRP诱导的突触消除。脆性X染色体综合征（FXS）是最常见的遗传性智力低下，也是导致自闭症的主要原因。FXS是由脆性X智力迟钝蛋白（FMRP）的功能突变丧失引起的。我们的研究将确定FMRP在大脑中的正常工作方式，以及没有FMRP的大脑功能如何以及为什么不同。这项工作有望为智力迟钝和自闭症的发展治疗提供重要的知识。

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.