Early-life sleep disruption in Shank3-deficient rats: A preclinical model for autism-related sleep mechanisms and interventions

Abstract Sleep disturbances are among the most prevalent and early-emerging features of autism spectrum disorder (ASD), often preceding core behavioral symptoms. Despite their clinical relevance, the neurobiological mechanisms driving early-life sleep disruption in ASD remain poorly understood. Shank3 , encoding a synaptic scaffolding protein at excitatory synapses, is one of the most well-established monogenic risk factors for ASD. Here, we systematically investigated sleep architecture and homeostatic regulation in juvenile Shank3 Δe11–21 rats, which lack Shank3 protein and display ASD-like behavioral and sensory phenotypes. EEG/EMG recordings revealed sex-specific abnormalities: males exhibited fragmented sleep with frequent brief arousals, whereas females showed prolonged wakefulness. Both sexes demonstrated reduced NREM sleep δ power, indicating diminished sleep depth. Following 6-h sleep deprivation, Shank3 −/− rats displayed blunted homeostatic rebound. Additionally, Clock and Bmal1 mRNA were significantly downregulated in prefrontal cortex and striatum, implicating circadian dysregulation within corticostriatal circuits. Collectively, these findings indicate that Shank3 deficiency leads to early-onset, low-quality sleep accompanied by impaired homeostatic and circadian regulation. This phenotype mirrors clinical sleep disturbances in children with ASD, supporting sleep dysfunction as an intrinsic, early feature of Shank3 -related pathophysiology. Together with prior behavioral evidence, this study establishes the Shank3 Δe11–21 rat as a preclinical model for elucidating mechanisms of Shank3 -related neurodevelopmental disorders and for evaluating potential early-life therapeutic interventions, including sleep-targeted strategies.