Using Genetically Modified Mutant Mice to Model Autism Spectrum Disorder and Determine Its Developmental Pathogenesis

Abstract

Numerous mouse models of autism spectrum disorder (ASD) have been generated to determine the molecular and circuit mechanisms underlying the condition. In this dissertation, I characterize the behavior of two mouse models mimicking some of the most common mutations found in human patients, which is an important step in establishing them as models. One important application of mouse models is our ability to use them to test specific treatments in a preclinical setting. These treatments are primarily pharmacological in nature, but some work has also been done to test the effects of the environment on the presentation of phenotypes. In particular, environmental enrichment has been shown to prevent the manifestation of ASD-like behaviors in several different mouse models of the disorder. In this dissertation, I tested the effects of environmental enrichment on our Shank3 mouse model of ASD and found that it did not rescue any of the behavioral phenotypes we previously observed, but rather exacerbated some common comorbidities.More recently, methods have been developed to manipulate gene expression in mice over space and time and have been utilized to gain a clearer picture of the cell types, circuits, brain regions, and developmental time periods involved in autism spectrum disorder. I utilized conditional knockout technology to test whether behavioral phenotypes associated with ASD could be induced by deleting Shank3 in adult and developing mice. We found that Shank3 may play a role in development and that inducing mutations in adult mice is insufficient to cause ASD-like behaviors. Unfortunately, technical concerns limit our interpretation of the data, and this study adds to the growing concern of the limitations inherent in this technology.