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 大型基因组研究的最新数据表明，拷贝数变化（CNV）是主要的 在精神疾病的病因中起关键作用的突变类别，包括自闭症（ASD）和精神分裂症 （SZ），最多增加30倍的风险。但是，CNV中的大量基因和各种各样的临床 与它们相关的表型使人们了解了CNV相关疾病及其基因型 - 表型 相关性特别具有挑战性。 16p11.2染色体区域的重复发生在ASD，SZ，智力中 残疾（ID），rolandic癫痫和其他疾病，并且是最高度渗透和频繁的CNV之一 在SZ。尽管基因组学取得了这种进展，但16p11.2 CNV模型中的突触表型尚未彻底 研究。稳健的突触表型的识别将导致实验上接近治疗的靶标 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，神经病理学和功能研究与树突状结构有关 神经发育精神疾病（包括SZ，ASD和ID）的发病机理。但是，突触生物学 有助于CNV疾病的发病机理仍然难以捉摸。在此续签应用中，我们建议 研究CNV对SZ，ASD和其他神经发育中的突触和树突功能障碍的影响 通过关注16p11.2复制来疾病。我们假设16p11.2基因座驱动器中的单个基因 通过调节定位 由CNV外基因编码的蛋白质。这些表型可以通过靶向网络中心来逆转。在这个 应用，我们将使用跨越培养的神经元，小鼠模型和患者衍生的INS的集成方法 在子宫电气中，尖端技术在内的尖端技术的组合 电生理学，蛋白质，多阵列电极记录和高内含成像屏幕，以追求以下 目的：1）16p11.2微解释障碍中突触子表型的机制； 2）机制 16p11.2微解症障碍中的基本树枝状亚型。 3）药理逆转16p11.2 重复表型。鉴于16p11.2重复是主要的，拟议的研究是新颖和有影响力的 尚未研究精神病危险因素及其突触危险因素。如果成功，该提议将是 第一个证明细胞子组合特异性蛋白质组学和高度渗透性单基因基因 可以利用CNV内的内部识别新型机制，从而使CNV内的驱动器可以调节蛋白质 CNV之外的网络。这种细胞区室特异性蛋白网络改变，不预测全局 mRNA分析可能是特定疾病亚表征的基础。这样的表型可以通过全球逆转 靶向网络中心，为治疗精神疾病的治疗开辟了新的策略。