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

Publisher: BioMed Central Country of Publication: England NLM ID: 101548963 Publication Model: Electronic Cited Medium: Internet ISSN: 2042-6410 (Electronic) Linking ISSN: 20426410 NLM ISO Abbreviation: Biol Sex Differ Subsets: MEDLINE

Original Publication: London : BioMed Central, 2010-

Nerve Tissue Proteins*/genetics ; Sex Characteristics* ; Mutation*; Animals ; Male ; Female ; Sleep ; Microfilament Proteins/genetics ; Mice ; Autism Spectrum Disorder/genetics ; Sleep Wake Disorders/genetics ; Sleep Deprivation/genetics ; Mice, Inbred C57BL

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.
(© 2024. The Author(s).)

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F99 NS135815 United States NS NINDS NIH HHS; 878115 Simons Foundation Autism Research Initiative; R56NS124805 United States NH NIH HHS; 1F99NS135815-01 United States NH NIH HHS; R56 NS124805 United States NS NINDS NIH HHS

Keywords: Autism spectrum disorder; Development; SHANK3; Sex differences; Sleep
Local Abstract: [plain-language-summary] Sleep problems are common in people with Autism Spectrum Disorder (ASD) and can make their condition worse, impacting both their lives and those of their caregivers. Historically ASD has been diagnosed more often in males and much less is known about the female phenotype. However, recent studies suggest that sleep problems may be more severe in autistic females. We previously shown that the ASD mouse model, Shank3 ^∆C , display an autism like sleep phenotype. Using this model, we examine sex specific deficits in sleep. We investigated canonical measures of sleep during undisturbed conditions (sleep architecture) and after sleep deprivation (sleep homeostasis).Our findings revealed that male Shank3 ^∆C mice slept less during their active period while female Shank3 ^∆C mice slept less during their rest period and more during their active period. In addition, both male and female Shank3 ^∆C mice displayed lower sleep quality. After sleep deprivation, both male and female Shank3 ^∆C mice took longer to fall asleep despite accumulation of sleep pressure, however, differences in sleep time after sleep deprivation differed based on sex. In healthy controls, sleep time increases after sleep deprivation. Male Shank3 ^∆C mice showed no such increase in sleep time, while female Shank3 ^∆C mice slept even less. Our results suggest sex specific differences in two hallmark measures of sleep, architecture and sleep homeostasis in this ASD model. These results highlight the importance of awareness of sex specific differences when studying sleep in ASD as well as eventual treatment or interventions.

0 (Shank3 protein, mouse)
0 (Nerve Tissue Proteins)
0 (Microfilament Proteins)

Date Created: 20241029 Date Completed: 20241029 Latest Revision: 20241105

20241106

PMC11514800

10.1186/s13293-024-00664-6

39468684