Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Recent genetic findings have identified mutations in synaptic cell adhesion genes and genes encoding their interacting protein partners at central synapses as genetic causes of autism spectrum disorders. We have created a novel autism model mouse line based on deletion of neuroligin-1. These mice have selective, excessive repetitive behavioral abnormalities of potential relevance to autism. Our preliminary data strongly implicate a decrease in NMDA receptor function in the striatum as a cause of this repetitive behavior phenotype. We now propose experiments to examine the effect of deletion of this gene on cortico-striatal synaptic function in detail. Furthermore, we propose to selectively rescue/treat this phenotype using genetic and pharmacologic approaches. Thus, we will be able to directly connect a specific synapse in a specific brain region due to a specific molecular abnormality with an abnormal behavior, an important basic goal in neuroscience. These experiments will identify novel synaptic and circuit-level mechanisms for obsessive-compulsive disorder- like repetitive behaviors in general. In addition, we hope to identify novel treatment targets for these behaviors for a subset of autistic patients.

Public Health Relevance

Our goal is to better understand genetic causes of human autism and to use animal models of such causes to identify treatments. This R01 proposal capitalizes on our recent progress examining a novel genetic autism- relevant model. This model exhibits excessive stereotyped repetitive behaviors characteristic of autism. Our experiments will directly link abnormalities in brain function in a specific brain region with these abnormal behaviors and allow us to identify novel treatment targets for a subset of autism and perhaps other disorders with obsessive-compulsive-like behavioral differences. Ultimately, such treatments could be tested directly in patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH093697-01A1
Application #
8235641
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gilotty, Lisa
Project Start
2012-08-01
Project End
2016-05-31
Budget Start
2012-08-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$397,396
Indirect Cost
$147,396
Name
University of Texas Sw Medical Center Dallas
Department
Neurology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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