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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH101198-03
Application #
8870439
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Asanuma, Chiiko
Project Start
2013-07-11
Project End
2018-05-31
Budget Start
2015-07-15
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
$385,000
Indirect Cost
$135,000
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Bakhurin, Konstantin I; Mac, Victor; Golshani, Peyman et al. (2016) Temporal correlations among functionally specialized striatal neural ensembles in reward-conditioned mice. J Neurophysiol 115:1521-32
Peñagarikano, Olga; Lázaro, María T; Lu, Xiao-Hong et al. (2015) Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med 7:271ra8
Lázaro, Maria T; Golshani, Peyman (2015) The utility of rodent models of autism spectrum disorders. Curr Opin Neurol 28:103-9
Srinivasan, Rahul; Huang, Ben S; Venugopal, Sharmila et al. (2015) Ca(2+) signaling in astrocytes from Ip3r2(-/-) mice in brain slices and during startle responses in vivo. Nat Neurosci 18:708-17
Garcia-Junco-Clemente, Pablo; Golshani, Peyman (2014) PTEN: A master regulator of neuronal structure, function, and plasticity. Commun Integr Biol 7:e28358
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

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