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.

抽象的 大规模基因组研究的最新数据表明，拷贝数变异（CNV）是一个主要的基因组变异。 在包括自闭症 (ASD) 和精神分裂症在内的精神疾病病因学中起关键作用的一类突变 (SZ)，风险增加高达 30 倍。然而，CNV中基因数量庞大，临床表现多种多样。 与它们相关的表型，使人们了解 CNV 相关疾病及其基因型-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、智力障碍中 残疾 (ID)、Rolandic 癫痫和其他疾病，是渗透率最高和最常见的 2 种 CNV 之一 在深圳。尽管基因组学取得了这一进展，但 16p11.2 CNV 模型中的突触表型尚未得到彻底研究。 研究过。强大的突触表型的鉴定将导致实验上可接近的治疗目标 神经精神疾病的常见方面，例如认知功能障碍。谷氨酸能突触的改变和 基因组学、神经病理学和功能研究表明，树突结构是树突状结构的关键位点。 神经发育精神疾病（包括 SZ、ASD 和 ID）的发病机制。然而，突触生物学 导致 CNV 疾病发病机制的因素在很大程度上仍然难以捉摸。在此续签申请中，我们建议 研究 CNV 对 SZ、ASD 和其他神经发育障碍的突触和树突功能障碍的影响 通过关注 16p11.2 重复引起的疾病。我们假设 16p11.2 基因座内的单个基因驱动 不同的亚表型，通常表示为细胞区室特异性改变，通过调节 由 CNV 之外的基因编码的蛋白质。这些表型可以通过针对网络中心来逆转。在这个 应用程序中，我们将使用涵盖培养神经元、小鼠模型和患者来源的 iN 的综合方法，以及 结合了 SIM 和双光子成像、子宫内电穿孔、切片等尖端技术 电生理学、蛋白质学、多阵列电极记录和高内涵成像屏幕，以追求以下目标 目的：1) 16p11.2 微重复紊乱中突触亚表型的潜在机制； 2）机制 16p11.2 微重复障碍中潜在的树突亚表型。 3) 16p11.2的药理逆转 重复表型。鉴于 16p11.2 重复是一个主要的，因此拟议的研究是新颖且有影响力的 精神危险因素及其突触树突影响尚未得到研究。如果成功，该提案将 第一个证明细胞亚区室特异性蛋白质组学和高渗透性单基因疾病基因 可以利用 CNV 内的驱动器来识别新的机制，从而 CNV 内的驱动程序可以调节蛋白质 CNV 之外的网络。这种细胞区室特异性蛋白质网络的改变，不是由全球预测的 mRNA 分析可能是特定疾病亚表型的基础。这种表型可以通过以下方式在全球范围内逆转： 以网络中心为目标，开辟治疗精神疾病的新策略。