Neurobiology of Aggression Comorbidity in Autism

自闭症攻击性合并症的神经生物学

基本信息

批准号：
10201418
负责人：
CLIFFORD B SAPER
金额：
$ 43.25万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-12 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201418
关键词：
15q 3-Dimensional Affect Aggressive behavior Alleles Axon Behavior Disorders Behavioral Binding Brain Cell Nucleus Cells Chromosomes Communication Complex Copy Number Polymorphism Cyclic AMP-Dependent Protein Kinases Cytoplasm Data Defect Development Dopamine Antagonists Dopamine D2 Receptor Electroconvulsive Therapy Electrophysiology (science)Epitopes FDA approved Family Feedback Foundations Gene Dosage Genes Genetic Genetic Models Genetic Transcription Glutamates Human Hypothalamic structure Injections Isodicentric Chromosome Knock-out Laboratories Learning Life Light Maps Medical Messenger RNA Mission Modeling Molecular Mus Mutation Neurobiology Neurons Nuclear Export Nuclear Import Peptides Pharmaceutical Preparations Phosphorylation Site Problem behavior Refractory Research Design Role Site Social Interaction Synapses Synaptic Transmission Territoriality Testing Transgenic Mice UBE3A gene Work autism spectrum disorder cell type comorbidity designer receptors exclusively activated by designer drugs disability insight interstitial male mimetics neural circuit neuronal cell body new therapeutic target novel novel therapeutic intervention postsynaptic preclinical study receptor reconstitution repetitive behavior therapeutic target therapy development tool transmission process ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Aggression is a frequent comorbidity in autism spectrum disorders (ASD). The problem is one of the major reasons families seek medical therapy. Understanding the molecular basis and deciphering the neural circuits that contribute to the development of this aggression comorbidity could inform novel targeted therapeutics. Increased copies of maternal chromosome 15q11-13 region [interstitial duplication with a single extra copy and extranumerary isodicentric chromosome 15q (Idic15) with two extra copies] are frequent and strongly penetrant (Idic15) causes of ASD. We have recently established that extra copies of Ube3a alone (15q11-13 gene expressed exclusively from maternal allele in neurons) are sufficient to reproduce ASD-like deficits in mice (Smith et al. 2011). Interestingly, mice with extra copies of Ube3a also show increased aggression. Taken together, these observations indicate that aberrant expression of Ube3a underlies multiple ASD-associated behavioral problems. In this project we will dissect Ube3a's role in controlling the aggression-comorbidity of ASD: 1) Identify specific neuronal cell types where increased Ube3a gene dosage increase aggression and identify underlying transcriptional and electrophysiological changes; and 2) Identify synaptic connections that are disrupted by increased Ube3a gene dosage to increase aggression within those neuronal cell types. The project promotes the agency's mission to further a deeper understanding of the neuronal cells, circuits, and genes involved in ASD via genetic models. The novel molecular insights and genetic tools will facilitate development of treatments for these life-long behavioral disabilities.

项目概要攻击性是自闭症谱系障碍 (ASD) 中常见的合并症。问题是其中之一家庭寻求药物治疗的主要原因。了解分子基础并破译神经网络有助于这种攻击性合并症发展的回路可以为新的目标提供信息疗法。母体染色体 15q11-13 区域拷贝数增加 [间质重复单个额外拷贝和具有两个额外拷贝的额外等双着丝粒染色体 15q (Idic15)] 是自闭症谱系障碍 (ASD) 的常见且强渗透性 (Idic15) 原因。我们最近确定了额外的副本单独的 Ube3a（仅由神经元中的母体等位基因表达的 15q11-13 基因）足以在小鼠中重现 ASD 样缺陷（Smith et al. 2011）。有趣的是，带有额外 Ube3a 拷贝的小鼠也表现出更强的攻击性。综上所述，这些观察表明，异常表达 Ube3a 是多种 ASD 相关行为问题的基础。在这个项目中我们将剖析 Ube3a 在控制自闭症谱系障碍的攻击性合并症中的作用：1）识别特定的神经元细胞类型，其中增加 Ube3a 基因剂量会增加攻击性并识别潜在的转录和电生理变化； 2) 识别因 Ube3a 增加而中断的突触连接基因剂量以增加这些神经元细胞类型内的攻击性。该项目促进了该机构的使命是进一步深入了解与 ASD 相关的神经元细胞、回路和基因遗传模型。新颖的分子见解和遗传工具将促进治疗方法的开发对于这些终生的行为障碍。