Neurobiology of Aggression Comorbidity in Autism

自闭症攻击性合并症的神经生物学

• 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
• 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

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 攻击是自闭症谱系障碍(ASD)的一种常见共病。这个问题是 家庭寻求医疗治疗的主要原因。了解分子基础并破译神经 有助于这种攻击性共病发展的回路可以告知新的靶向 治疗学。母体染色体15q11-13区拷贝数增加[间质复制 单个额外拷贝和外等双着丝粒染色体15q(Idic15)加上两个额外拷贝]是 ASD的常见和强渗透性原因(Idic15)。我们最近确定了额外的副本 仅Ube3a(15q11-13基因在神经元中仅由母系等位基因表达)就足以 在小鼠中复制类似ASD的缺陷(Smith等人2011年)。有趣的是，携带额外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， 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的 在控制ASD的攻击性-共病中的作用：1)确定特定的神经细胞类型 增加Ube3a基因剂量增加攻击性并识别潜在的转录和 电生理变化；以及2)确定Ube3a增加扰乱的突触连接 在这些神经细胞类型中增加攻击性的基因剂量。该项目促进了该机构的 使命通过以下途径进一步深入了解ASD涉及的神经细胞、电路和基因 遗传模型。新的分子洞察力和基因工具将促进治疗方法的开发 为这些终生的行为障碍。