AN INVESTIGATION OF THE BEHAVIORAL DEFICITS AND NEURAL DISRUPTIONS PRESENT IN THE SHANK3B +- KNOCKOUT MOUSE MODEL OF AUTISM

Abstract

Autism Spectrum Disorder (ASD) is a multifactorial neurodevelopmental disorder that presents a broad array of socio-communicative deficits and repetitive behaviors. Though ASD may arise from different environmental or genetic factors, it is hypothesized that atypical functional connectivity is the fundamental underlying cause. Indeed, it is theorized that the execution of behaviors requires the systematic recruitment and activation of different brain regions, and that disruptions in the flow of neural information across the brain impair cognition and produce atypical behavioral phenotypes. In this thesis study, we used a mouse model of ASD to explore the relationship between altered neural motifs and disrupted behavioral phenotypes. To accomplish this, we characterized the repetitive behaviors, social deficits, and neural dysfunction of mice expressing the Shank3b+- knockout genetic mutation. Our analyses revealed that KO mice exhibit repetitive self-grooming behaviors, but do not engage in repetitive digging. Our data also indicated that social deficits are only present during the recently-weaned juvenile stage. Preliminary analysis of widefield mesoscale calcium imaging revealed that there are significant differences in the whole-brain neural dynamics of Shank3b+- knockout mice. We also introduced two novel behavioral assays, which gave insight into the sex-based differences in the phenotypic expression of ASD. Altogether, this work provides a new understanding of the behavioral deficits and altered neural activity found in the Shank3b+- knockout mouse model of ASD.