NEUROMORPHOLOGICAL ABNORMALITIES AND SLEEP DISRUPTIONS MAY AFFECT CORE SYMPTOMS IN THE GENETIC MOUSE MODEL OF ASD

Beyond core symptoms, individuals with autism spectrum disorder (ASD) experience sleep disturbances. These findings are replicated in ASD animal models, including Shank3-deficient mice. Poor sleep can worsen primary symptoms in many conditions and has been linked to brain abnormalities in ASD. However, whether disrupted sleep exacerbates ASD symptoms or represents a separate issue remains unclear. To investigate, we assessed sleep in Shank3B^-/- and wild-type (WT) mice of both sexes (n=8/group) using 24-hour monitoring. We further evaluated sociability, repetitive behavior, locomotion, anxiety-like behavior, and cognition via traditional behavioral testing. Mice underwent MRI (T₂-w) for brain region-specific volumetry to identify structural abnormalities. Shank3B^-/- mice exhibited three times more repetitive grooming (p<0.001), 50% less social interaction (p<0.05), twice as much social disinterest (p<0.05), and twice as much anxiety-like behavior (p<0.05) compared to WTs. While total sleep was comparable, Shank3B^-/- mice experienced twice as many sleep disruptions (p<0.001). A higher frequency of sleep disruptions correlated with increased anxiety-like behavior (r=-0.69, p=0.003), more repetitive grooming (r=0.53, p=0.04), and reduced sociability (r=-0.48). Additionally, Shank3B-/- mice exhibited reduced relative volumes of hypothalamus, hippocampus, striatum, corpus callosum, and cerebellum (p<0.05). Structural differences selectively correlated with poor sleep, impaired long-term memory, and reduced sociability. Our findings suggest that sleep disruptions may mediate severity of ASD symptoms in Shank3-deficient mice. Further studies employing sleep deprivation and controlling for potential confounding factors, such as social isolation, are needed to confirm. If validated, targeting sleep could offer a promising approach for alleviating ASD symptoms in both preclinical and clinical settings.