Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

Abstract

Sleep disruption is a common comorbidity in patients with autism spectrum disorder (ASD), a condition diagnosed with a striking male bias of ~4:1. It is unclear how sleep disruption contributes to ASD susceptibility, and the sex biased vulnerability. We examined sleep behavior and the effects of early life sleep disruption (ELSD) in developing mice bearing C-terminal truncation (ΔC) in ASD risk gene Shank3. Male and female Shank3ΔC/ΔC homozygotes showed clear sleep disruption early in postnatal life, compared to Shank3WT/ΔC heterozygotes and wild-type littermates, suggesting that sleep disruption may be an early symptom in the expression of ASD. We find that ELSD interacts with genetic vulnerability in Shank3WT/ΔC heterozygotes to drive lasting and sex-specific changes in behavior. Our results clearly show that sleep disruption during sensitive periods of postnatal development is causative of lasting changes in behavior in genetically vulnerable individuals, but in a striking sex-specific manner.

Loss of sleep when it is needed most – Consequences of persistent developmental sleep disruption: A scoping review of rodent models

“…1 , Table 1 , Table 2 ). Cage manipulation includes cage-shaking using an orbital shaker ( Jones et al, 2019a ; Lord et al, 2022 ) or insertion of novel objects to force locomotion ( Li et al, 2017 ). Cage manipulation presents the opportunity for potential automated disruption that is either continuous, targeting only the light-phase (when rodents are most likely to be asleep), and/or using closed loop delivery of disruption based on EEG/EMG activity ( Jones et al, 2019a , 2019b , 2020 , 2021 ; Lord et al, 2022 ; Bian et al, 2022 ; Feng et al, 2000 ; Nagai et al, 2021 ).…”

“…Cage manipulation includes cage-shaking using an orbital shaker ( Jones et al, 2019a ; Lord et al, 2022 ) or insertion of novel objects to force locomotion ( Li et al, 2017 ). Cage manipulation presents the opportunity for potential automated disruption that is either continuous, targeting only the light-phase (when rodents are most likely to be asleep), and/or using closed loop delivery of disruption based on EEG/EMG activity ( Jones et al, 2019a , 2019b , 2020 , 2021 ; Lord et al, 2022 ; Bian et al, 2022 ; Feng et al, 2000 ; Nagai et al, 2021 ). An animal's cage includes its light source, the developmental chronic circadian disruption (DCCD) paradigm mimics severe shift-work with the light cycle advances dramatically every other or every fourth day ( Smarr et al, 2017 ; Ameen et al, 2022 ).…”

“…Shank3 ΔC is a mutant form of the Shank3 gene with exon 21 truncated and an established model of ASD. Shank3 ΔC mice showed reduced time asleep at juvenile (P25-41) and adolescent (P42-56) timepoints, using a piezo home-cage monitoring system as a proxy for sleep phenotyping ( Lord et al, 2022 ). Using EEG/EMG recordings, Shank3 ΔC mice showed less total sleep across development with increased amounts of REM sleep than controls at P23, P29, P59 in the light phase, accompanied by reductions in NREM sleep ( Medina et al, 2022 ).…”

“…During sleep manipulations, not all studies validated DSD with the gold standard EEG/EMG recordings. Some paradigms were validated based on video scoring or cage-activity, finding differences in rest (bout) duration, but without EEG-based sleep staging ( Lord et al, 2022 ; Ameen et al, 2022 ). The timing and duration of sleep disruption is also an important consideration in assessing the behavioral and neuropathological consequences.…”

“…The timing and duration of sleep disruption is also an important consideration in assessing the behavioral and neuropathological consequences. Some paradigms adhered to a specific, well-justified period of development ( Lord et al, 2022 ), whereas others spanned multiple stages of development ( Saré et al, 2019 ). When comparing different manipulations, it will be essential to keep in mind the exact developmental window under study ( Fig.…”