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)：据估计，超过6%的美国人(或近1900万人)患有严重的精神障碍。许多此类疾病发生在发育或青春期，强有力的证据支持，它们是由基因突变或基因拷贝数变化引起或加剧的。治疗方法是存在的，但几乎没有治愈的方法。人类遗传学研究发现，CYFIP1是一种基因，在包括某些形式的Angelman和Prader-Willi综合征、自闭症谱系障碍和精神分裂症在内的各种发育性大脑疾病中处于失调状态。单个基因是如何导致如此多的疾病的？CYFIP1是一种细胞质蛋白，胞质FMRP相互作用蛋白，具有两个独立且高度保守的功能。CYFIP1作为一种非规范的起始因子4E结合蛋白(4E-BP)抑制FMRP靶mRNAs的帽依赖翻译，并作为波复合体的一个组成部分调节质膜上分支肌动蛋白细丝的产生。已知对帽依赖翻译和肌动蛋白细胞骨架的调节对突触组装、形态和可塑性都很重要，也被认为是易受发育性大脑疾病影响的途径。因此，很容易理解为什么即使只丢失一个拷贝的CYFIP1也会产生广泛的后果，但对于CYFIP1在突触发育中的功能还没有很好的了解。在这项建议中，我们将使用我们开发的表达降低水平的CYFIP1的小鼠模型来研究CYFIP1如何对突触的发育、功能和可塑性做出贡献。初步实验表明，CYFIP1水平降低的神经元在发育过程中表现出一种强烈的、主要是突触前的表型，这种表型在青春期缺失，而在青春期则表现出同样强大的突触后表型，这在年轻动物中是缺失的。基于这些发现，我们将检验这一假说，即CYFIP1的S在帽子依赖的蛋白质合成和肌动蛋白聚合中的作用对发育过程中的突触前功能和成熟时的突触后生理和可塑性有不同的贡献。