A Behavioral and Molecular Approach for Understanding Angelman Syndrome

Abstract

Autism Spectrum Disorder (ASD) is a set of human developmental disorders that affects ~1 in 68 children. The clinical features of ASD include deficits in social behavior and frequent co-morbidity of motor, emotional and sensory impairment. Currently, there are no effective treatments. A major obstacle for treating ASD is the limited knowledge of the neuronal circuits that drive these complex behaviors. Several monogenic, or single-gene, disorders that possess similar features to ASD have been identified, implicating a role for molecular pathways in the development of these behavioral circuits. This dissertation focuses on Angelman Syndrome (AS), a neurodevelopmental disorder characterized by social communication deficits, movement disorder and hyper-excitable behavioral traits. The phenotype of AS arises from mutation of the UBE3A gene, encoding an E3 ubiquitin ligase. The overarching goal of this study is to understand how deregulation of UBE3A-dependent pathways contribute to the behavioral phenotype of AS. Neuronal substrates of UBE3A have been identified and their expression has been shown to be up-regulated in AS neurons. I now test the hypothesis that this deregulation contributes to specific pathology of AS. First, I described clinically relevant behavioral phenotypes in an AS mouse model. Next, I genetically reduced the expression level of two UBE3A substrates, ARC (Activity-Regulated Cytoskeleton-Associated Protein) and EPHEXIN5 (Rho Guanine Nucleotide Exchange Factor 15) in the AS mouse and assayed for reversal of behavioral abnormalities. I find that the AS mouse model has impaired communication and motor behavior during early postnatal development, enhanced seizure-like activity and an abnormal cortical electroencephalogram (EEG). Reducing the levels of ARC reversed the enhanced seizure-like activity and EEG, but not the communication or motor deficits. The specific rescue of seizure-like activity by reducing ARC, but not EPHEXIN5, reveals a role for molecular diversity in the development of behavioral circuits. Further, these findings suggest that therapeutic interventions that reduce the level of ARC expression have the potential to reverse the seizures associated with AS. Lastly, the identification of aberrant behaviors in AS mice provides clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder, and broader ASDs.