INVESTIGATING SLEEP PROBLEMS IN AUTISM SPECTRUM DISORDER USING THE SHANK3∆C MOUSE MODEL

Elizabeth Medina

Up to 93% of individuals with the neurodevelopmental disorder autism spectrum disorder (ASD) experience symptoms of insomnia, including increased sleep latency, increased night awakenings, and a reduction in total sleep time. ASD is characterized by two core symptoms: social communication deficits and restrictive, repetitive behaviors. The etiology of ASD, however, arises from a complex interplay of genetic susceptibility and environmental factors. Sleep loss leads to widespread molecular and cellular changes in the brain, which are associated with alterations in neuronal growth and the regulation of behavior. While symptoms of insomnia in the general population are more prevalent in females, ASD is disproportionally diagnosed in males. In addition, problems falling asleep in infant siblings of individuals with ASD precede an ASD diagnosis and accompany an altered trajectory of brain development. Therefore, a comprehensive understanding of sleep regulation in ASD and the molecular consequences of sleep loss is vital to defining the role of sleep in neurodevelopmental disorders such as ASD. Genetic mouse models of ASD provide powerful insight into the mechanisms underlying the disorder. We have previously demonstrated that adult mice carrying a mutation in the high-confidence autism gene Shank3∆C exhibit an abnormal transcriptional response following sleep loss and are the only ASD mouse model that recapitulate all features of the clinical autism sleep phenotype. We hypothesized that sleep problems are likely a core feature of ASD and have adversely long term consequences on brain function. The focus of this thesis is to utilize the Shank3∆C mouse model to elucidate how age and sex may alter sleep disturbances and the molecular consequences of sleep loss in ASD. Collectively, the findings in this dissertation demonstrate that sleep differences are sex-dependent and detectable in early life in the Shank3∆C mouse model. These findings identify key biological functions that are altered after sleep loss, thus enhancing our understanding of the mechanistic link between sleep and ASD. The findings of this thesis can be leveraged to improve sleep or minimize the impact of sleep loss in individuals with ASD, thereby enhancing their quality of life.

INVESTIGATING SLEEP PROBLEMS IN AUTISM SPECTRUM DISORDER USING THE SHANK3∆C MOUSE MODEL

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