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: 8825186
• 负责人: Deanna L Benson
• 金额: $ 42.38万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825186
• 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; Hippocampus (Brain); Human Development; 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; dosage; gain of function; in vivo; juvenile animal; mouse model; multidisciplinary; mutant; neural circuit; novel; polymerization; postsynaptic; presynaptic; public health relevance; 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）：据估计，超过6%的美国人（或近1900万人）患有严重的精神障碍。许多这类疾病出现在发育或青春期，强有力的证据表明，它们是由基因突变或基因拷贝数变异引起或加剧的。虽然有治疗方法，但治愈的方法却很少。人类遗传学研究已经确定CYFIP1是一种在多种发育性脑疾病（包括某些形式的Angelman综合征和prder - willi综合征、自闭症谱系障碍和精神分裂症）中失调的基因。一个基因是如何导致这么多疾病的？CYFIP1产生细胞质蛋白，细胞质FMRP相互作用蛋白（CYFIP1），具有两个独立且高度保守的功能。Cyfip1作为一种非规范起始因子4E结合蛋白（4E- bp）抑制FMRP靶mrna的帽依赖翻译，并作为WAVE复合体的一个组成部分调节质膜上分支肌动蛋白丝的产生。帽依赖翻译和肌动蛋白细胞骨架的调节对于突触的组装、形态和可塑性都是重要的，也被认为是易受发育性脑疾病影响的途径。因此，我们很容易理解为什么即使是单个Cyfip1拷贝的丢失也会产生广泛的后果，但Cyfip1在突触发育中的功能却没有得到很好的理解。在本提案中，我们将使用我们开发的表达Cyfip1水平降低的小鼠模型来研究Cyfip1如何促进突触的发育、功能和可塑性。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突触前表型，这在青春期是缺失的，在青春期表现出同样强烈的突触后表型，这在年轻动物中是缺失的。基于这些发现，我们将验证Cyfip1在帽依赖蛋白合成和肌动蛋白聚合中的作用对发育期间的突触前功能和成熟时的突触后生理和可塑性有差异的假设。