Mouse Models of Autism to Discover Causes and Develop Treatments

Searching for the causes and cures for autism depends on strong animal models.  As candidate genes linked to autism are identified, mice with targeted mutations of these genes are becoming available.  Model organisms offer useful translational tools to test hypotheses about single genes, chromosomal locus deletions, copy number variants, epigenetic DNA methylation, neuroanatomical abnormalities, immune dysfunctions, diets, environmental toxins, and other proposed causes of autism.  

The key to successful translational applications is robust, highly replicable functional assays.  Our laboratory has generated a constellation of mouse behavioral paradigms with conceptual analogies to the three diagnostic symptoms of autism.  This presentation will focus on behavioral tests for mice that offer reasonable face validity to the defining symptoms of autism.  The core deficit in reciprocal social interactions is modeled longitudinally across developmental stages with juvenile and adult reciprocal social interaction scoring and automated social approach paradigms.  Communication in mice is investigated with measures of the emission, detection, and responses to olfactory and auditory social cues. Motor stereotypies, repetitive behaviors, insistence on sameness, and narrow restricted interests are analyzed in mice by quantitating spontaneous stereotyped motor behaviors, repetitive self-grooming, perseveration during the reversal phase of T-maze and Morris water maze spatial tasks, and restricted exploration of complex environments.  

Behavioral assays relevant to the associated symptoms of autism, including anxiety, seizures, sleep disruption, low IQ, and hyperreactivity to sensory stimuli, may provide further insights into the phenotypes of a mouse model of autism spectrum disorders.  Comprehensive control tests for general health, motor functions, and sensory abilities are conducted, to detect potential confounds due to physical defects, thus avoiding overinterpretations of artifacts.  

Both forward genetics and reverse mouse genetics are employed in our laboratory to understand the genetic basis of social, communication, and repetitive behaviors.  Results from knockout mice with targeted mutations in candidate genes for autism will be described.   BTBR T+tf/J, an inbred strain that displays autism-like traits on many of these tasks, will be used to illustrate phenotypes of a robust mouse model of autism.  

Targeted gene mutations and inbred strains of mice that incorporate traits with face validity to the diagnostic and associated symptoms of autism offer attractive model systems to evaluate potential treatments.  Early preclinical results will be presented on drug treatments and environmental interventions that reverse components of the autism-relevant behavioral phenotypes in the BTBR mouse model of autis