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.

Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice

“…It has been previously reported that cognitive and social performance can be negatively affected due to increased anxiety or sensory deficits (Kazdoba et al, 2016). Importantly, we found no abnormalities in visual function as assessed by the visual cliff test (Figure 5A).…”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…Although knockout, knockin, or transgenic approaches of autism-risk genes in animal models have demonstrated some of the autistic-like behaviors (Kazdoba et al, 2016), the limitation of the number of genes being manipulated in animals makes it difficult to recapitulate the human condition experimentally. Furthermore, ASD is a common comorbid condition in individuals with other neurodevelopmental disorders.…”

Autism and Cancer Share Risk Genes, Pathways, and Drug Targets

“…Some of these mutant mouse models recapitulate behavioral and biological features of autism [13]. These model systems are proving useful in understanding the consequences of specific mutations on overgrowth of brain regions, unusual patterns of white matter connectivity, aberrant numbers of synapses, and altered morphology of dendritic spines, in parallel to understanding cell proliferation, cell cycle, DNA repair, and epigenetic causes in malignancies.…”