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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.

项目总结