Sleep problems are prevalent in autism spectrum disorder (ASD), can be observed before diagnosis, and are associated with increased restricted and repetitive behaviors. Therefore, sleep abnormalities may be a core feature of the disorder, but the developmental trajectory remains unknown. Animal models provide a unique opportunity to understand sleep ontogenesis in ASD. Previously we showed that adult mice with a truncation in the high‐confidence ASD gene Shank3 (Shank3∆C) recapitulate the clinical sleep phenotype. In this study we used longitudinal electro‐encephalographic (EEG) recordings to define, for the first time, changes in sleep from weaning to young adulthood in an ASD mouse model. We show that Shank3∆C male mice sleep less overall throughout their lifespan, have increased rapid eye movement (REM) sleep early in life despite significantly reduced non‐rapid eye movement (NREM) sleep, and have abnormal responses to increased sleep pressure that emerge during a specific developmental period. We demonstrate that the ability to fall asleep quickly in response to sleep loss develops normally between 24 and 30 days in mice. However, mutants are unable to reduce sleep latency after periods of prolonged waking and maintain the same response to sleep loss regardless of age. This phenomenon seems independent of homeostatic NREM sleep slow‐wave dynamics. Overall, our study recapitulates both preclinical models and clinical studies showing that reduced sleep is consistently associated with ASD and suggests that problems falling asleep may reflect abnormal development of sleep and arousal mechanisms.

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Sleep deprivation (SD) results in profound cellular and molecular changes in the adult mammalian brain. Some of these changes may result in, or aggravate, brain disease. However, little is known about how SD impacts gene expression in developing animals. We examined the transcriptional response in the prefrontal cortex (PFC) to SD across postnatal development in male mice. We used RNA sequencing to identify functional gene categories that were specifically impacted by SD. We find that SD has dramatically different effects on PFC genes depending on developmental age. Gene expression differences after SD fall into 3 categories: present at all ages (conserved), present when mature sleep homeostasis is first emerging, and those unique to certain ages in adults. Developmentally conserved gene expression was limited to a few functional categories, including Wnt-signaling which suggests that this pathway is a core mechanism regulated by sleep. In younger ages, genes primarily related to growth and development are affected while changes in genes related to metabolism are specific to the effect of SD in adults.

Sleep problems are prevalent in Autism Spectrum Disorder (ASD), can be observed before diagnosis and are associated with increased restricted and repetitive behaviors. Therefore, sleep abnormalities may be a core feature, but the developmental trajectory remains unknown. Previously we showed that adult mice with a truncation in Shank3 (Shank3ΔC) recapitulate the ASD sleep phenotype (Ingiosi et al, 2019). In this study we used longitudinal electro-encephalographic recordings to define, for the first time, changes in sleep from weaning to young adulthood in an ASD mouse model. We show that Shank3ΔC mice sleep less throughout their lifespan and have abnormal responses to increased sleep pressure during a specific developmental period. More specifically, mutants appear unable to rapidly enter sleep, despite preceding periods of prolonged waking. Overall, our study indicates that reduced sleep is a core feature of ASD and suggests that problems falling asleep reflect abnormal development in sleep and arousal mechanisms.