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

Researchers studied sleep problems in rats with autism-like features caused by missing a protein called Shank3. They found that male rats had broken, restless sleep while female rats stayed awake too long. Both had poor quality sleep and couldn't recover properly after being kept awake. The rats also had problems with their body clock genes in brain areas linked to autism.

These sleep issues were similar to what's seen in autistic children, suggesting sleep problems start early and are a core part of this type of autism.

This preclinical study examined sleep patterns in juvenile Shank3-deficient rats, a well-established autism model. Researchers used EEG/EMG recordings to assess sleep architecture and found sex-specific abnormalities: males showed fragmented sleep with frequent brief awakenings, while females experienced prolonged wakefulness. Both sexes demonstrated reduced deep sleep (NREM δ power) and impaired sleep homeostatic rebound following deprivation. The study also identified downregulation of circadian clock genes (Clock and Bmal1) in prefrontal cortex and striatum, suggesting circadian dysfunction in brain circuits important for autism.

These findings mirror clinical sleep disturbances observed in autistic children and support the concept that sleep dysfunction is an intrinsic, early feature of Shank3-related autism pathophysiology.

Findings support early sleep intervention in autism and suggest sex-specific approaches may be needed. The identification of circadian gene dysfunction in specific brain regions provides potential therapeutic targets. Results validate sleep dysfunction as an intrinsic early feature of autism rather than a secondary consequence.

This is a preclinical animal study, so findings may not directly translate to humans. Sample size was not reported, making it difficult to assess statistical power. The study focused on one specific genetic model of autism (Shank3 deficiency), which may not represent all forms of autism.

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 Shank3rats, 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, Shank3rats 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 Shank3rat as a preclinical model for elucidating mechanisms of Shank3-related neurodevelopmental disorders and for evaluating potential early-life therapeutic interventions, including sleep-targeted strategies.