UC Berkeley

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, and the presentation of restricted repetitive patterns of behavior. The prevalence of ASD has increased steadily in the last 40 years, with a recent study from the Center for Disease Control (CDC) indicating that roughly 1 in 36 children in America is diagnosed with ASD. The disorder has a strong genetic component, and there have now been over 100 high confidence ASD risk genes identified through genetic sequencing of those with ASD. As improved genetic tools allow for these genes to be identified, genetic access in animal models has also improved, allowing for the development of many mouse models of ASD that harbor mutations in these identified genes. ASD risk genes vary greatly in the types of proteins for which they encode, including ion channels, neurotransmitter receptors, cell adhesion molecules, and machinery implicated in all aspects of transcription and translation. Despite this genetic heterogeneity, the major diagnostic criteria of ASD still fit within the two symptom domains listed above. Given this shared symptomology, much work in ASD research has focused on identifying brain regions that may be commonly impacted across a range of underlying genetic alterations. The basal ganglia, in particular the striatum, the primary input center of the basal ganglia, has arisen as one such brain region. We believe that dysfunction of the striatum, given its known role in action selection, motor learning, and habit formation, may be particularly implicated in the restricted, repetitive behavior domain of ASD. However, whether altered striatal function is a shared pathophysiology across genetically diverse ASD mouse models has yet to be comprehensively assessed. For this dissertation project, I investigated this question in two unique ASD mouse models. First, I developmentally deleted the ASD risk gene Tsc1 selectively from the two primary types of striatal projection neurons (SPNs). I found that loss of Tsc1 selectively from SPNs of the direct pathway (dSPNs), but not the indirect pathway (iSPNs), increases cortical drive of these neurons, likely through increased glutamate release from cortical inputs onto these cells. This increased corticostriatal drive of the direct pathway increases motor learning, measured through enhanced performance in the accelerating rotarod assay. Altered cortical input to the striatum has arisen as a potential convergent change across a number of ASD mouse models, an idea that is reviewed and expanded upon in the second chapter of this dissertation. To investigate whether striatal function and striatum-associated behaviors are altered in a genetically distinct mouse model, I utilized mice with brainwide loss of the ASD risk gene Cntnap2. I found that mice lacking Cntnap2 also exhibited increased cortical drive, of both dSPNs and iSPNs. In this model however, cortical synaptic input onto SPNs was unchanged. Instead, the intrinsic excitability of SPNs in Cntnap2-/- mice was significantly increased, in particular in dSPNs, which likely underlies the increased cortical drive of these cells. Behaviorally, Cntnap2-/- mice also exhibit increased performance in the accelerating rotarod task, as well as increased spontaneous repetitive behaviors, and cognitive inflexibility in a reversal learning task. Together, these findings support a role for striatal dysfunction in the manifestation of stereotyped, inflexible behaviors across ASD mouse models with varying genetic causes. In particular, this data supports an emerging theory that corticostriatal alterations, in particular enhanced cortical activation of the movement-initiating direct pathway, may occur commonly in the case of ASD-associated repetitive behaviors.