Sleep disturbances during early development alter key synaptic proteins involved in autism spectrum disorder.
Anyone who has ever put a toddler to bed knows it’s a struggle. While sleep might be the bane of a toddler’s existence it is also an essential component for their brain development. Toddlers need an average of 11-14 hours of sleep a day (1). During that sleep, synaptic connections in toddlers’ brains begin to mature.
In a recent study published in the Proceeding of the National Academy of Sciences, Graham Diering, assistant professor in the Department of Cell Biology and Physiology at the University of North Carolina at Chapel Hill, and a team led by graduate student Sean Gay, found that sleep disturbances during development in young mice affect the regulation of key synaptic proteins implicated in autism (2). Synapses are small protein-filled spaces between neurons that allow them to communicate.
“Synapses are where memories are made and stored, and a lot of research has shown that synapses are part of the business end of what sleep is for,” said Diering. Sleep and synaptic plasticity also play a role in learning and neurodevelopmental disorders. Many autism-associated genes encode synaptic proteins. People with autism spectrum disorder also experience significant sleep disturbances.
In a previous study in 2022, Diering and his team explored the effect of disrupting sleep in three-week old mice (roughly equivalent to age 1-2 in humans), that were genetically predisposed to develop autism. Disrupting sleep during early brain development caused long-lasting changes in the social behaviors of adult mice. However, if these mice experienced no sleep disturbances, then they developed behaviors more akin to their wildtype siblings (3), clearly implicating sleep in autism spectrum disorder development.
“It’s clear that in most cases, [autism spectrum disorder] is not a purely genetic condition. It’s really an interaction with other environmental factors,” said Diering. In their recent study, Diering and Gay wanted to better understand the molecular cost of sleep loss during development and its interaction with autism risk genes. To do this they turned to wildtype mice. The team disturbed the sleep of wildtype three-week-old and adult mice for four hours by tapping on their cages any time the mice dozed off.
After the four hours of sleep disruption, the adult mice resumed sleeping and even slept more than usual during their normal wake times. “The way I like to phrase that for people to appreciate easily is that they stayed up past bedtime and slept in the next day. It’s a very familiar behavior, and we see this across all different species,” said Diering.
The big surprise for the team was that that the young mice who experienced disturbed sleep progressed through the day as normal without ever making up for the lost sleep. A lack of sleep also caused impaired memory function in young mice the next day.
To get at the molecular underpinnings of these observations, Diering’s team extracted the mice’s forebrains, including the cortex and hippocampus, key areas needed for higher cognitive function and memory. They isolated and molecularly analyzed synapses from these brain regions and found that sleep deprivation in juvenile, but not adult mice impacted important aspects of brain maturation such as synaptogenesis.
They also found that many known autism-risk proteins were upregulated in the synapses of sleep deprived young mice. Some of these proteins aid in forming the perineural net, an area located outside of cells that acts like a cell scaffold.
“In the developing brain, these extracellular matrix proteins are what I call wet cement. They’re basically forming as the brain is growing, and then once you exit development, these structures become hardened and last the rest of your life,” said Diering. “It was kind of a surprise, but it really informs our thinking about how sleep disruption during development can contribute to lasting phenotypes.”
One night of poor sleep though is unlikely to cause lasting effects. The mechanism underlying the link between sleep and autism is complex, cumulative, and influenced by both genetics and the environment. “Now, we know what are some key vulnerabilities that we can look to expand in our disease context, and hopefully make a bigger breakthrough on how sleep disruption in the autism context contributes to lasting behavior changes,” said Diering.
His team is continuing to investigate the proteins that emerged from their recent study. They have also made some other intriguing findings of how sleep influences changes in adolescence and the aging brain. “The field has been after this holy grail for a long time of what’s the function for sleep,” said Diering. “Our research is really pushing this kind of new view that sleep doesn’t just do one thing your whole life. There are actually different functions for sleep. To me that’s one of the biggest wins.”
References
- How much sleep is enough? National Heart Lung, and Blood Institute https://www.nhlbi.nih.gov/health/sleep/how-much-sleep (2022).
- Gay, S.M. et al. Developing forebrain synapses are uniquely vulnerable to sleep loss. Proc Natl Acad Sci 121 (2024).
- Lord, J. et al. Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice. Mol Autism 13(35) (2022).
Written by Tiffany Garbutt, PhD
For more on this study, read the UNC School of Medicine’s coverage here