PROJECT SUMMARY Autism spectrum disorder (ASD) is a common neurodevelopmental condition that affects social behavior and cognitive flexibility. Sleep disruption is a common comorbidity in ASD, observed in more than 80% of affected individuals. It has been debated whether sleep disruption in ASD is a consequence of altered brain function, or whether sleep disruption is actually a core component of ASD and driver of altered brain function and behavior. Sleep disruption is often seen in advance of ASD diagnosis, and the severity of sleep disruption can be predicative of the severity of other ASD associated phenotypes, strongly suggesting that sleep disruption is an early symptom in ASD and a potential driver of the condition. Multiple studies, including new work from our lab, have shown in animal models (rodents and fruit flies) that a period of early life sleep disruption is causal in long- lasting and sex-specific changes in social and cognitive behaviors in adults. Thus, developmental sleep disruption is emerging as an important contributor to ASD susceptibility. Alterations in synapse number, structure, and function have been documented repeatedly in ASD models and patient samples, leading many to describe ASD as a “synaptophathy”: a dysfunction of synapse function. Consistent with this assertion, gene sequencing efforts have identified hundreds of risk genes associated with ASD, many of which encode proteins with known synaptic functions, such as the excitatory synaptic scaffold protein SHANK3. Another important cluster of ASD risk genes encode for proteins with nuclear functions such as CHD8. Sleep has been shown to be critical for synapse formation, maturation and elimination in the developing brain. Therefore, we hypothesize that synapse maturation is a critical vulnerability to the consequences of developmental sleep disruption. We have recently published that early life sleep disruption (ELSD) can cause long-lasting and sex-specific changes in behavior in the genetically vulnerable Shank3(+/C) heterozygous mice, whereas wild type littermates were found to be resilient (Lord et al., 2022, Molecular Autism). To determine if developmental sleep disruption is broadly relevant in ASD we must test whether ELSD similarly interacts with distinct genetic vulnerabilities. CHD8 is a high-confidence ASD risk gene that encodes a nuclear chromatin remodeling enzyme. CHD8 is believed to play an important role in brain development during embryogenesis, but whether CHD8 mutation also confers vulnerability to postnatal sleep disruption has not been tested. We will determine whether ELSD drives lasting changes in behavior in genetically vulnerable Chd8(+/V986*) ASD model mice, similarly to what we have recently demonstrated with heterozygous Shank3 ASD model mice. We will also examine whether postnatal synapse maturation is a convergent node of vulnerability to developmental sleep disruption. Our goals in this R21 proposal is to establish developmental slee...