Developmentally sensitive regulatory mechanisms of synapse assembly and function

突触组装和功能的发育敏感调节机制

• 批准号: 9158651
• 负责人: Deanna L Benson
• 金额: $ 0.42万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9158651
• 关键词: Actins; Adolescence; Adolescent; Affect; American; Binding; Binding Proteins; Brain; Brain Diseases; Cell membrane; Complex; Copy Number Polymorphism; Cytoplasmic Protein; Cytoskeleton; Data; Defect; Development; Disease; Equilibrium; FMRP; Future; Gene Dosage; Gene Mutation; Generations; Genes; Genetic; Genetic study; Health; Hippocampus (Brain); Human; Human Genetics; Individual; Kinetics; Long-Term Potentiation; Mediating; Messenger RNA; Microfilaments; Modeling; Morphology; Mus; Mutation; Neurons; Pathway interactions; Patients; Peptide Initiation Factors; Phenotype; Physiology; Play; Prader-Willi Syndrome; Property; Protein Biosynthesis; Proteins; Psyche structure; Publishing; Recycling; Regulation; Risk; Role; Schizophrenia; Severity of illness; Synapses; Synaptic Vesicles; Testing; Translations; Variant; Vesicle; Work; autism spectrum disorder; base; course development; dosage; gain of function; in vivo; juvenile animal; mouse model; multidisciplinary; mutant; neural circuit; novel; polymerization; postsynaptic; presynaptic; research study; severe mental illness; synaptic function; synaptogenesis; therapeutic development; tool

DESCRIPTION (provided by applicant): It is estimated than more 6% of all Americans (or nearly 19 million individuals) suffer from a serious mental disorder. Many such disorders arise during development or adolescence, and strong evidence supports that they are caused or exacerbated by gene mutations or variations in gene copy number. Treatments exist, but there are few cures. Human genetic studies have identified CYFIP1 as a gene that is dysregulated in a wide variety of developmental brain disorders including certain forms of Angelman and Prader-Willi syndromes, autism spectrum disorders, and schizophrenia. How does a single gene contribute to so many disorders? CYFIP1 produces a cytoplasmic protein, cytoplasmic FMRP interacting protein (Cyfip1), having two independent and highly conserved functions. Cyfip1 represses cap-dependent translation of FMRP target mRNAs as a noncanonical initiation factor 4E binding protein (4E-BP), and it regulates the generation of branched actin filaments at the plasmalemma as an integral component of the WAVE complex. Regulation of both cap-dependent translation and actin cytoskeleton are known to be important for synapse assembly, morphology, and plasticity and are also known to be pathways that are vulnerable to developmental brain disorders. Thus it is easy to appreciate why loss of even a single copy of Cyfip1 could have broad consequences, but the function of Cyfip1 at developing synapses is not well understood. In this proposal we will investigate how Cyfip1 contributes to synapse development, function, and plasticity using a mouse model we developed expressing reduced levels of Cyfip1. Preliminary experiments show that neurons with reduced Cyfip1 levels display a strong, principally presynaptic phenotype during development that is missing in adolescence, and an equally strong, but postsynaptic phenotype in adolescence that is missing in younger animals. Based on these findings, we will test the hypothesis that Cyfip1's actions in cap-dependent protein synthesis and actin polymerization contribute differentially to presynaptic function during development and postsynaptic physiology and plasticity in maturity.

描述（由申请人提供）：估计它比所有美国人（或近1900万人）的6％遭受严重的精神障碍。许多这样的疾病在发育或青春期期间出现，有力的证据支持它们是由于基因突变或基因拷贝数的变化而引起或加剧的。存在治疗，但是几乎没有治疗方法。人类遗传学研究已将CYFIP1鉴定为一种基因，在多种发育性脑部疾病中失调，包括某些形式的Angelman和Prader-Willi综合征，自闭症谱系疾病和精神分裂症。单个基因如何导致如此多的疾病？ CYFIP1产生细胞质蛋白，细胞质FMRP相互作用蛋白（CYFIP1），具有两个独立和高度保守的功能。 CYFIP1抑制了FMRP靶MRNA作为非规范起始因子4E结合蛋白（4E-BP）的cap依赖性翻译，并且它调节了血浆处的分支肌动蛋白丝的产生，作为波络合物的组成部分。众所周知，对帽依赖性翻译和肌动蛋白细胞骨架的调节对于突触组装，形态和可塑性很重要，并且也被称为容易受到发育脑部疾病的途径。因此，很容易理解为什么即使单个CYFIP1副本的丢失也可能产生广泛的后果，但是Cyfip1在开发突触中的功能尚不清楚。在此提案中，我们将使用小鼠模型来研究CYFIP1如何为突触的发展，功能和可塑性贡献，我们开发出表达降低的CYFIP1水平。初步实验表明，CYFIP1水平降低的神经元在发育过程中表现出强烈的，主要是突触前的表型，并且在青春期缺失，并且在青春期中同样强但同样强的突触后表型，而在年轻动物中则缺少。基于这些发现，我们将检验以下假设：CyFIP1在帽依赖性蛋白质合成中的作用和肌动蛋白聚合在发育期间和突触后生理学和成熟性的可塑性过程中有不同的贡献。