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.

Public Health Relevance

Autism spectrum disorder (ASD) is a heterogeneous group of related behavioral disorders, characterized by deficits in three core domains: communication and social interaction, and repetitive behaviors and often co-morbid irritability/aggression. This project seeks to learn how increases of Ube3a, a gene within a frequent genetic copy number variant found in human ASD (maternal 15q11-13 duplication) affects the expression of other genes to alter brain circuit functions underlying increased aggression. Understanding the genetic and circuit defects that underlie increased aggression will provide therapeutic targets to treat the comorbidity.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Winsky, Lois M
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Beth Israel Deaconess Medical Center
United States
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