Behavioral phenotypes of genetic mouse models of autism

Abstract

More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism.

Keywords: Anxiety-like; autism; cognition; genes; hyperactivity; mice; mutant models; neurodevelopmental; repetitive behavior; sensory reactivity; sociability; social behavior; vocalizations.

Figure 1. Examples of rodent behavioral assays with face validity to the diagnostic symptoms of autism

(a) Two mice interacting in a Noldus Phenotyper 3000 reciprocal social interaction chamber equipped with an Avisoft ultrasonic microphone. The inset shows representative ultrasonic vocalizations recorded during adult male–female social interaction. (b) Close-up of two mice displaying ‘crawl over and under’ during the reciprocal social interaction test session. (c) 3-Chambered social approach apparatus offers automated scoring of time spent with a novel social partner vs. time spent with a novel object. (d) BTBR mouse engaged in repetitive self-grooming. Photos by Jane Hayes, Michael Pride, Jill Silverman and Mu Yang, MIND Institute, University of California Davis School of Medicine.