Shank3 mutation disrupts the molecular signature of sleepiness across development
Background: Sleep problems are common in autism, emerge early in life and reduce quality of life, yet the mechanistic link between autism and poor sleep remains unclear. Human and rodent data indicate that difficulty falling asleep is a core feature of autistic insomnia, pointing to impaired responses to sleepiness as the underlying cause. We previously showed that adult mice carrying a mutation…
Sleep disturbances are prevalent among individuals with autism, emerging early in life and negatively impacting their quality of life. Despite the known link between autism and poor sleep, the specific mechanisms remain uncertain. Rodent studies suggest that difficulty falling asleep may be a core symptom of autistic insomnia, indicating impaired sensitivity to sleepiness as the root cause.
Previous research demonstrated that adult mice with a mutation in the Shank3 gene, a well-established autism-associated gene (Shank3{Delta}C), displayed insomnia-like symptoms and difficulties responding to sleepiness following acute sleep deprivation. To further investigate the molecular basis of sleepiness and how this specific Shank3 mutation influences it, researchers utilized Shank3{Delta}C mice in this study.
The scientists employed RNA sequencing and bioinformatics to identify molecular targets affected by the Shank3{Delta}C mutation on sleepiness regulation across different developmental stages in male mice. First, they compared the overall gene expression patterns in the cortex of adult wild-type (WT) and mutant mice following acute sleep deprivation and subsequent recovery sleep.
Subsequently, they utilized polysomnography and RNA sequencing to evaluate the response to increased sleepiness in both WT and mutant mice at postnatal days 24 and 30.
The study revealed a neurotypical response to acute sleep deprivation, which shifts from upregulating pathways associated with neuronal growth and development during early postnatal days (P24/P30) to upregulating DNA damage repair and neuronal activity-dependent transcription in adulthood. However, the Shank3{Delta}C mutation largely inhibited the recruitment of these pathways in early postnatal mice and, paradoxically, amplified the mutant response to sleep deprivation at P30.
Moreover, the mutant mice consistently showed heightened upregulation of oxidative stress pathways, linked to neurodegeneration and protein synthesis, irrespective of age. In contrast, WT mice downregulated these functions.
While the study provides valuable insights into the molecular underpinnings of sleep disturbances in autism associated with Shank3{Delta}C mutation, it has several limitations. The research was conducted solely in male mice, used a single rodent model for autism, and averaged signals across various cortical cell types. Future research should incorporate both males and females, investigate additional autism models, and employ single-cell approaches in multiple brain regions to further elucidate the cellular effects of sleep deprivation and autism-related genetic mutations.
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