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：
9416303
负责人：
MATTHEW P ANDERSON
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/9416303
关键词：
15q Affect Aggressive behavior Alleles Alpha Cell Autistic Disorder Axon Behavior Disorders Behavioral Binding Brain Cell Nucleus Cells Chromosomes Communication Comorbidity Complex Copy Number Polymorphism Cyclic AMP-Dependent Protein Kinases Cytoplasm Data Defect Development 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 Injectable Injection of therapeutic agent 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 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.

项目摘要侵略是自闭症谱系障碍（ASD）的常见合并症。问题是家庭寻求药物治疗的主要原因。了解分子基础并解密神经有助于发展这种侵略性合并症的电路可以告知新颖的目标疗法。增加母体染色体15q11-13区域的副本[与A的间隙重复单个额外的副本和外部等级染色体15q（IDIC15），带有两个额外的副本] ASD的频繁且强烈渗透（IDIC15）。我们最近确定了额外的副本仅Ube3a（仅由神经元中的母体等位基因表达的15q11-13基因）就足够在小鼠中繁殖ASD样缺陷（Smith等，2011）。有趣的是，带有ube3a额外副本的老鼠还显示出攻击性的增加。综上所述，这些观察结果表明 UBE3A是多个与ASD相关的行为问题的基础。在这个项目中，我们将剖析Ube3a的在控制ASD的攻击性刺激性方面的作用：1）确定特定的神经元细胞类型 UBE3A基因剂量增加增加了攻击性并确定基本的转录和电生理变化； 2）确定因UBE3A而破坏的突触连接基因剂量增加了这些神经元细胞类型中的攻击性。该项目促进了该机构的使命是进一步了解ASD涉及的神经元细胞，电路和基因遗传模型。新颖的分子见解和遗传工具将促进治疗的发展对于这些终身行为残疾。