Sex differences in sleep deficits in mice with an autism-linked Shank3 mutation.

Abstract

Background: Insomnia is more prevalent in individuals with Autism Spectrum Disorder (ASD), can worsen core-symptoms and reduces quality of life of both individuals and caregivers. Although ASD is four times more prevalent in males than females, less is known about sex specific sleep differences in autistic individuals. Recent ASD studies suggest that sleep problems may be more severe in females, which aligns with the sex bias seen in insomnia for the general population. We have previously shown that male mice with a mutation in the high confidence ASD gene Shank3, Shank3^∆C, recapitulate most aspects of the ASD insomnia phenotype. The objective of the present study was to leverage the Shank3^∆C model to investigate sex-specific effects in sleep using polysomnography.

Methods: Adult male and female Shank3^∆C and wildtype (WT) littermates were first recorded for 24 h of baseline recordings. Subsequently, they were sleep deprived (SD) for five hours via gentle handling and allowed 19 h of recovery sleep to characterize the homeostatic response to SD. Vigilance states (rapid eye movement (REM) sleep, non-rapid eye movement (NREM) sleep and wake) were assigned by manual inspection using SleepSign. Data processing, statistical analysis and visualization were conducted using MATLAB.

Results: Sex and genotype effects were found during baseline sleep and after SD. At baseline, male Shank3^∆C mice sleep less during the dark period (active phase) while female Shank3^∆C mice sleep less during the light period (rest phase) and sleep more during the dark period. Both male and female Shank3^∆C mice show reduced spectral power in NREM sleep. We detect a significant effect of sex and genotype in sleep onset latency and homeostatic sleep pressure (sleepiness). In addition, while male Shank3^∆C mice fail to increase sleep time following SD as seen in WT, female Shank3^∆C mice decrease sleep time.

Conclusions: Overall, our study demonstrates sex differences in sleep architecture and homeostatic response to SD in adult Shank3^∆C mice. Thus, our study demonstrates an interaction between sex and genotype in Shank3^∆C mice and supports the use of the Shank3^∆C model to better understand mechanisms contributing to the sex differences in insomnia in ASD in clinical populations.