Synaptic and dendritic dysfunction in psychiatric disorders

精神疾病中的突触和树突功能障碍

• 批准号: 9402750
• 负责人: Peter Penzes
• 金额: $ 60.32万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402750
• 关键词: 16p11.2; Affinity; Antineoplastic Agents; Architecture; Autistic Disorder; Behavior; Bioinformatics; Biological; Biology; Categories; Copy Number Polymorphism; Data; Disease; Electrophysiology (science); Electroporation; Epilepsy; Etiology; Exhibits; Functional disorder; Funding; Gene Expression; Genes; Genomics; Genotype; Glutamate Receptor; Glutamates; Image; Impaired cognition; Individual; Intellectual functioning disability; Ion Channel; Lighting; MAPK3 gene; Manuscripts; Mendelian disorder; Mental disorders; Messenger RNA; Microscopy; Modeling; Molecular; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Ontology; Pathogenesis; Pathogenicity; Pathway Analysis; Patients; Pharmacology; Phenotype; Play; Proteins; Proteomics; Psychiatric therapeutic procedure; Publishing; Risk; Risk Factors; Rolandic Epilepsy; SNAP receptor; Schizophrenia; Site; Slice; Structure; Synapses; Synaptosomes; Technology; Vertebral column; base; brain morphology; clinical phenotype; in utero; induced pluripotent stem cell; insight; mouse model; multi-electrode arrays; neuropsychiatric disorder; novel; novel strategies; prevent; therapy development; trafficking; two-photon

ABSTRACT Recent data emerging from large-scale genomic studies has revealed that copy number variations (CNVs) are a major class of mutations that play a key role in the etiology of psychiatric disorders, including autism (ASD) and schizophrenia (SZ), increasing risk up to 30 fold. However, the large number of genes in CNVs, and the wide variety of clinical phenotypes associated with them, has made understanding CNV-associated disorders and their genotype-phenotype correlations especially challenging. Duplications of 16p11.2 chromosomal region, occur in ASD, SZ, intellectual disability (ID), Rolandic epilepsy, and other disorders, and are among the top 2 most highly penetrant and frequent CNVs in SZ. Despite this progress in genomics, synaptic phenotypes in models of 16p11.2 CNV have not yet been thoroughly studied. The identification of robust synaptic phenotypes would result in experimentally approachable targets for treating common aspects of neuropsychiatric disorders such as cognitive dysfunction. Alterations in glutamatergic synapses and dendritic architecture have been implicated by genomic, neuropathological, and functional studies as key sites of pathogenesis in neurodevelopmental psychiatric disorders including SZ, ASD, and ID. However, the synaptic biology that contributes to the pathogenesis of CNV disorders remains largely elusive. In this renewal application we propose to investigate the impact of CNVs on synaptic and dendritic dysfunction in SZ, ASD and other neurodevelopmental disorders by focusing on the 16p11.2 duplication. We hypothesize that individual genes within the 16p11.2 locus drive distinct sub-phenotypes, often expressed as cellular compartment-specific alterations, by modulating localization of proteins encoded by genes outside the CNV. These phenotypes can be reversed by targeting network hubs. In this application, we will use an integrated approach spanning cultured neurons, mouse models, and patient-derived iNs, and a combination of cutting-edge technologies including SIM and two-photon imaging, in utero electroporations, slice electrophysiology, protemics, multi-array electrode recordings, and high-content imaging screens, to pursue the following Aims: 1) Mechanisms underlying synaptic sub-phenotypes in 16p11.2 microduplication disorder; 2) Mechanisms underlying dendritic sub-phenotypes in 16p11.2 microduplication disorder. 3) Pharmacological reversal of 16p11.2 duplication phenotypes. The proposed studies are novel and impactful, given that the 16p11.2 duplication is a major psychiatric risk factor and its synapto-dendritic impact has not yet been investigated. If successful, this proposal will be the first to demonstrate that cellular subcompartment-specific proteomics and highly penetrant monogenic disease genes within the CNV can be harnessed to identify novel mechanisms whereby a driver within the CNV can regulate a protein network outside of the CNV. Such cellular compartment-specific protein network alterations, not predicted by global mRNA profiling, could underlie specific disease sub-phenotypes. Such phenotypes could be be reversed globally by targeting network hubs, opening novel strategies for the treatment of psychiatric disorders.

摘要 来自大规模基因组研究的最新数据表明，拷贝数变异(CNV)是主要的 在包括自闭症(ASD)和精神分裂症在内的精神疾病的病因学中起关键作用的一类突变 (深圳)，风险增加高达30倍。然而，CNV中的大量基因，以及广泛的临床应用 与它们相关的表型，使人们了解了CNV相关疾病及其基因-表型 相关性尤其具有挑战性。16p11.2染色体区域重复，发生在ASD、SZ、SCHART 残疾(ID)、罗兰迪克癫痫和其他疾病，是最高渗透性和最常见的两个CNV之一 在深圳。尽管基因组学取得了这些进展，但16p11.2CNV模型中的突触表型尚未完全确定 学习。对强健突触表型的鉴定将导致实验上可接近的治疗靶点 神经精神障碍的常见方面，如认知功能障碍。谷氨酸能突触的改变和 树突状结构已被基因组、神经病理学和功能研究作为关键部位所牵连。 神经发育精神障碍的发病机制包括SZ、ASD和ID。然而，突触生物学 在CNV疾病的发病机制中的作用在很大程度上仍然难以捉摸。在此续期申请中，我们建议 探讨CNV在SZ、ASD和其他神经发育中突触和树突功能障碍中的作用 通过关注16p11.2重复而引起的疾病。我们假设16p11.2基因座内的单个基因驱动 不同的亚表型，通常表现为细胞间隔室特异性的改变，通过调节 由CNV外的基因编码的蛋白质。这些表型可以通过瞄准网络枢纽来逆转。在这 应用程序，我们将使用一种集成的方法，跨越培养的神经元、小鼠模型和患者衍生的INS，以及 结合包括SIM和双光子成像在内的尖端技术，宫内电穿孔，切片 电生理学、质子学、多阵列电极记录和高内容成像屏幕，以追求以下目标 目的：1)16p11.2微复制障碍突触亚型的潜在机制；2)机制 16p11.2微复制障碍的树突状亚型。3)16p11.2基因的药理逆转 复制表型。鉴于16p11.2复制是一个主要的 精神危险因素及其对突触-树突状细胞的影响尚未被研究。如果成功，这项提议将是 首次证明细胞亚室特异性蛋白质组学和高穿透性单基因疾病基因 可以利用CNV内的驱动程序来识别新的机制，从而CNV内的驱动程序可以调节蛋白质 CNV之外的网络。这种细胞间隔室特有的蛋白质网络改变，没有被全球 信使核糖核酸谱，可能是特定疾病亚型的基础。这些表型可以通过以下方式在全球范围内逆转 瞄准网络枢纽，开启治疗精神障碍的新策略。