Chronic sleep disruption is a major comorbidity seen in more than 80 percent of children with autism spectrum disorder (ASD). Sleep disruption is often seen in advance of a diagnosis and is 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.

Recent research shows that early life sleep disruption (ELSD) interacts with genetic vulnerability in Shank3 (WT/deltaC) heterozygous mice to cause long lasting and sex-specific changes in behavior¹. Genetically vulnerable Shank3 heterozygotes were not affected by post-development sleep disruption, showing that early life is uniquely vulnerable. Sleep has been shown to be essential in the formation, maturation and elimination of synapses during critical period plasticity^{^2}. Thus, Graham Diering and colleagues hypothesize that ELSD, combined with underlying genetic vulnerability, negatively affects the maturation of synapses, leading to lasting changes in brain function and behavior.

Diering’s lab has recently developed a quantitative proteomics methodology to identify sleep sensitive processes in developing synapses³. Preliminary data shows that the synapse proteome and phosphoproteome are profoundly impacted by acute sleep deprivation in developing mice, but that adults are largely protected. Therefore, the major goals of this project are to identify nodes of vulnerability to ELSD in the developing synapse. Shank3 (WT/deltaC) heterozygotes and wild-type littermates will be exposed to ELSD conditions, and quantitative proteomics will be used to examine changes in the synapse proteome and phosphoproteome. The researchers also plan to examine the synapse proteome in the more severe Shank3 (deltaC/deltaC) homozygous mice to investigate whether Shank3 mutations and sleep disruption converge on common mechanisms. Identification of the nodes of vulnerability to developmental sleep disruption is an important step in developing sleep-based medicines for children with ASD.

1. Lord J.S. et al. Mol. Autism 13, 35 (2022) PubMed
2. Li W. et al. Nat. Neurosci. 20, 427–437 (2017) PubMed
3. Gay S.M. et al. bioRxiv (2024) Preprint