Common and rare mutations in contactin-associated protein-like 2 (CNTNAP2) are strongly linked to autism, with autosomal recessive truncating mutations resulting in autism in more than two-thirds of patients. However the alterations in functional connectivity underlying CNTNAP2-associated autism are not understood. Recently our collaborators demonstrated that a knockout mouse model of CNTNAP2 shows GABAergic interneuron migration abnormalities, robust social behavioral deficits, repetitive behaviors, communication problems, and seizures, accurately modeling the human condition. Here we propose to test the hypothesis that local and long- range functional medial prefrontal cortical connectivity is altered in the CNTNAP2 model of autism and that optogenetic interventions that correct the altered connectivity will improve social behavior. Finally, as gamma- synchronization has been hypothesized to underlie the abnormal cortical function in autism, potentially serving as a biomarker for diagnosis and gauging response to treatment, we will test the hypothesis that CNTNAP2 mice show altered gamma coherence between mPFC and amygdala, leading to altered recruitment of specific interneuron types in these structures. These hypotheses will be tested using single and paired patch clamp recordings from identified pyramidal and interneurons in combination with optogenetic stimulation or silencing of specific long-range projections, both in-vitro and in-vivo. These discoveries will guide the development of circuit-specific treatments for social behavioral deficits in ASD.

Public Health Relevance

Autism spectrum disorders affect over 1% of the population and cause suffering for patients and their families. Abnormal social behavior in autism may be caused by under-connectivity of specific long- range connections in the brain. This project will determine whether abnormal social behavior in a validated model of autism can be treated by functionally correcting this under-connectivity.

National Institute of Health (NIH)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Asanuma, Chiiko
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Mantoan Ritter, Laura; Golshani, Peyman; Takahashi, Koji et al. (2014) WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55:1693-702
Garcia-Junco-Clemente, Pablo; Golshani, Peyman (2014) PTEN: A master regulator of neuronal structure, function, and plasticity. Commun Integr Biol 7:e28358
Garcia-Junco-Clemente, Pablo; Chow, David K; Tring, Elaine et al. (2013) Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism. Proc Natl Acad Sci U S A 110:18297-302