Shank3 influences mammalian sleep development

Abstract

Sleep problems are prevalent in autism spectrum disorder (ASD), can be observed before diagnosis, and are associated with increased restricted and repetitive behaviors. Therefore, sleep abnormalities may be a core feature of the disorder, but the developmental trajectory remains unknown. Animal models provide a unique opportunity to understand sleep ontogenesis in ASD. Previously we showed that adult mice with a truncation in the high‐confidence ASD gene Shank3 (Shank3∆C) recapitulate the clinical sleep phenotype. In this study we used longitudinal electro‐encephalographic (EEG) recordings to define, for the first time, changes in sleep from weaning to young adulthood in an ASD mouse model. We show that Shank3∆C male mice sleep less overall throughout their lifespan, have increased rapid eye movement (REM) sleep early in life despite significantly reduced non‐rapid eye movement (NREM) sleep, and have abnormal responses to increased sleep pressure that emerge during a specific developmental period. We demonstrate that the ability to fall asleep quickly in response to sleep loss develops normally between 24 and 30 days in mice. However, mutants are unable to reduce sleep latency after periods of prolonged waking and maintain the same response to sleep loss regardless of age. This phenomenon seems independent of homeostatic NREM sleep slow‐wave dynamics. Overall, our study recapitulates both preclinical models and clinical studies showing that reduced sleep is consistently associated with ASD and suggests that problems falling asleep may reflect abnormal development of sleep and arousal mechanisms.

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

“…Serial EEG assessment of sleep and wake across the second postnatal week of life in mice reveals greater consistency of EEG spectral activity, fewer transitions in behavioral state and a decline in time spent in REM sleep ( Rensing et al, 2018 ) (Graphical Abstract 1a). Between P23 and P29, wildtype (WT) mice spend less time in NREM and REM in the dark period, and theta power in wake and REM decreases steadily ( Medina et al, 2022 ). Throughout this period, the brain continues to mature, REM sleep serves to promote this maturation and plasticity in later development ( Mirmiran, 1995 ).…”

“…These features are best provoked through additional sleep challenges, 3-h sleep deprivation generates increased sleep time and continuity in P12–P20 rats, though delta power only increases beginning at P24 ( Ribeiro et al, 1999 ). WT mice expectedly show increased sleep across development (serially assessed between P23 – P59) following 3-h of sleep deprivation ( Medina et al, 2022 ). The amount of REM-rebound following deprivation also increases with developmental age (from 2-week old to 4-week old) ( Cao et al, 2020 ).…”

“…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 ). Animal manipulation involves either gentle handling ( Medina et al, 2022 ; Weisman et al, 2011 ; Saré et al, 2016 , 2019 , 2022a ; Araujo et al, 2018 ; Yang et al, 2012 ; Murack et al, 2021 ) when the animal enters a sleep state, placing the animal on a platform over water where they are required to stay awake to avoid falling into the water ( da Silva Rocha-Lopes et al, 2018 ; Shaffery et al, 2006 ; Shaffery et al, 2002 ; Chen et al, 2015 ), or installing a sweeping bar that moves through the cage to enforce wakefulness ( Wallace et al, 2015 ; Atrooz et al, 2019 ). Pharmacological manipulation involves administration of a drug (e.g.…”

“…While this review focused on postnatal DSD, a few notable studies of genetic models of neurodevelopmental disorders have shown striking parallels to findings seen in classic DSD paradigms. Genetic manipulation includes creation of transgenic animals with mutant circadian clock expression ( Liu et al, 2022 ; Singla et al, 2022 ) or risk genes for neurodevelopmental disorders, ( Medina et al, 2022 ; Saré et al, 2017 , 2022a ). Circadian clock gene mutations have been implicated in ASD, thought to contribute to sleep-wake and social dysfunction (reviewed by ( Lorsung et al, 2021 )).…”

“…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 ). When challenged with a sleep deprivation protocol, Shank3 ΔC mice at P30 showed longer latency to recovery sleep, thought to be consistent with an insomnia phenotype common in ASD.…”