Summary: Deficiencies in the SHANK3 gene are associated with sleep disturbances in both people with autism spectrum disorder (ASD) and in mouse models. Patients with Phelan-McDermid syndrome—a genetic condition linked to SHANK3 and often associated with autism—report trouble falling and staying asleep. In mouse models, animals lacking part of the Shank3 gene experienced poorer deep sleep quality and spent more time awake during periods when control mice slept.
Source: Washington State University
Up to 80 percent of children with autism spectrum disorder (ASD) experience sleep problems, which can worsen core symptoms and strain families. A team of neuroscientists at Washington State University has identified a likely biological contributor: disruptions in the SHANK3 gene that appear to affect sleep regulation and circadian-related gene expression. Their work, published in the open access journal eLife, links SHANK3 loss to difficulty falling asleep and altered sleep-related gene activity, offering a clearer path toward targeted interventions.
“Poor sleep is not only a problem for individuals with autism but is also one of the top concerns among caregivers,” said Lucia Peixoto, an assistant professor at the WSU Elson S. Floyd College of Medicine and the study’s senior author. “There is a clear connection between sleep problems and the severity of autism’s core features—social and communication challenges and repetitive behaviors. Addressing the root of sleep disruption could reduce these downstream symptoms.”
The research combined human clinical data and detailed experiments in a mouse model. First, the team analyzed sleep information from people with Phelan-McDermid syndrome (PMS), a condition frequently associated with autism and linked to SHANK3 deletions. They found that children with PMS who lack SHANK3 commonly have trouble initiating sleep and experience frequent nighttime awakenings beginning around age five.
“Many kids with Phelan-McDermid syndrome sleep less than six hours a night, and their sleep remains poor across their lifespan, making it a persistent challenge,” said postdoctoral researcher and co-first author Hannah Schoch.
Co-first author Ashley Ingiosi conducted the mouse studies using animals missing exon 21 of Shank3 and compared them with wild-type controls. Under a standard 12-hour light / 12-hour dark cycle, Shank3 mutant mice spent more time awake toward the end of the dark phase, when nocturnal animals normally begin to nap. The mutants also showed indications of reduced deep-sleep quality.
To probe sleep drive versus sleep ability, the team performed sleep deprivation experiments. All mice were kept awake for the first five hours of their main sleep period. Both mutant and control mice accumulated sleep pressure to similar degrees, indicating the mutants were just as sleepy. However, Shank3 mutant mice took roughly twice as long to fall asleep as wild-type mice, suggesting the problem is initiating sleep rather than lacking sleepiness.
RNA sequencing of prefrontal cortex tissue revealed decreased expression of multiple circadian transcription factors in Shank3 mutants, including Per3, Bhlhe41, Hlf, Tef, and Nr1d1. Sleep deprivation amplified these differences: the number of genes failing to respond normally was about twice as large in sleep-deprived mutants compared with sleep-deprived wild types. These results suggest that sleep loss magnifies molecular differences associated with SHANK3 deficiency, which could worsen symptoms in people with PMS or autism.
Finally, the researchers examined daily activity rhythms. Although reduced circadian gene expression in Shank3 mutants did not alter the timing of rest-activity cycles, it did lead to decreased overall activity levels, a surprising effect that highlights complex links between SHANK3, circadian biology, and behavior.
Future work by the team will address whether sleep abnormalities in Shank3 mutant mice are present from birth or emerge during development, and will seek the molecular mechanisms by which SHANK3 mutations disrupt sleep. “If we can pinpoint the molecular pathways underlying sleep problems in Shank3 mutants, those insights should translate to sleep disturbances in autism more broadly and reveal new targets for intervention,” Peixoto said.
Funding: This research was supported by a grant from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health.
Source:
Washington State University
Media Contacts:
Lucia Peixoto – Washington State University
Image Source:
The image is in the public domain.
Original Research: Open access. “Shank3 modulates sleep and expression of circadian transcription factors.” Authors: Ashley M. Ingiosi, Hannah Schoch, Taylor Wintler, Kristan G. Singletary, Dario Righelli, Leandro G. Roser, Elizabeth Medina, Davide Risso, Marcos G. Frank, Lucia Peixoto. eLife. DOI: 10.7554/eLife.42819
Abstract
Shank3 modulates sleep and expression of circadian transcription factors
Autism Spectrum Disorder (ASD) is a common neurodevelopmental condition that frequently co-occurs with sleep disturbances. Poor sleep in ASD predicts greater severity of core diagnostic symptoms and imposes a heavy burden on caregivers. The molecular bases of these sleep problems are not well understood. This study examined the role of Shank3, a high-confidence ASD candidate gene, in sleep architecture and regulation. Mice lacking exon 21 of Shank3 had difficulty falling asleep despite being physiologically sleepy. RNA-seq analysis showed that sleep deprivation increased differences in prefrontal cortex gene expression between mutants and wild types, notably downregulating circadian transcription factors Per3, Bhlhe41, Hlf, Tef, and Nr1d1. Shank3 mutants also showed altered regulation of activity in constant darkness. Collectively, the findings identify Shank3 as an important modulator of sleep and circadian gene expression.