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Sleep cells: The genes linked to autism CHD7 and CHD8 are strongly expressed (yellow, middle and right columns) in the glia (pink and blue, left column)
The difficulty sleeping some people with autism experience may be due in part to leaks in the barrier that protects the brain from any toxins or pathogens in the blood, according to a new fruit fly study.
The work also suggests that behavioral treatment for chronic insomnia may help alleviate sleep problems in some people with autism.
“Sleep restriction therapy is a first-line treatment for insomnia, but in the clinic, for genetic syndromes or neurodevelopmental disorders, it is hardly ever applied,” explains principal investigator Annette Schenck, professor of Translational Genomics of Neurodevelopmental Disorders at Radboud University Medical. Center of Nijmegen, the Netherlands. “We hope that can change in the near future. “
Sleep problems occur in 50 to 80 percent of children with autism or other neurodevelopmental disorders, compared to about 20 percent of their neurotypical peers. To learn more about the roots of these problems, the researchers focused on data from 27 people with mutations in CHD7 or CHD8, two closely related genes that are strongly linked to autism and sleep problems.
The data came from a sleep clinic, the Simons Simplex Collection, a repository of genetic and trait information from families with an autistic child, and a University of Washington study titled The Investigation of Genetic Exome Research. . (The Simons Simplex Collection is funded by the Simons Foundation, Spectrumparent organization of.)
People with autism with mutations in CHD7 or CHD8 showed much more difficulty falling and staying asleep than about 2,300 autistic controls without a known autism-related mutation, according to the study. And three people with CHD7 mutations and one person with a CHD8 mutation suffered from chronic insomnia.
Glia surprise:
The researchers then focused on Kismet, the version of CHD7 and CHD8 found in fruit flies. Insects with a mutated copy of the gene had reduced and fragmented sleep like that seen in people with CHD7 or CHD8 mutations. Suppressing Kismet’s expression only in neurons did not trigger any problems with sleep, the researchers found, but its cancellation in the glial cells supporting neurons during development in flies did.
“Glia are really overlooked – they’re the sad, neglected stepchildren of the brain,” says Annika Barber, assistant professor of molecular biology and biochemistry at Rutgers University in New Jersey, who did not attend the study. “This work throws a fascinating spotlight on a group [of cells] not often thought of in neurodevelopmental disorders.
The flies’ sleep problems were specifically linked to the subperineural glia, a group of around 300 cells that help form the insect’s blood-brain barrier.
“These cells have not been previously reported as a cause of sleep fragmentation,” explains Schenck. “Instead, it is well established that sleep loss impairs the function of the blood brain barrier in certain neurological disorders. So apparently the regulation of sleep and the blood brain barrier are closely related, and so far we’ve only known half the story.
Levels of the neurotransmitter dopamine, which is the key to sleep and wakefulness, were not altered in flies lacking Kismet in glia, other experiments have shown. But these flies had unusually high levels of another neurotransmitter, serotonin, during development.
Using a drug to suppress serotonin levels in flies during development alleviated their sleeping difficulties. The increase in serotonin levels in wild type flies during development has resulted in sleep problems in adulthood. The results were published in June in Scientists progress.
A condition called hyperserotonemia, characterized by high levels of serotonin, is often linked to autism, although it is not known why. The new findings could rekindle interest in the role of serotonin in autism, particularly in how it can cross the blood-brain barrier, says Georgianna Gould, associate professor of cellular and integrative physiology at the Science Center of health from the University of Texas at San Antonio, which was not involved in this work.
Mutations that eliminate CHD7 or CHD8 are extremely rare, but “they may be representative of more common blood-brain barrier deficiencies that arise from several other origins,” Gould adds.
Simple interventions:
In a latest set of experiments, researchers developed an insect version of sleep restriction therapy, initially limiting the amount of darkness that insects feel, then gradually increasing it.
The team found that controlling darkness and light in this way helped solve sleep problems for model flies.
Sleeping difficulties in people with autism can exacerbate cognitive problems, leading to more difficulty sleeping, says Krishna Melnattur, assistant professor of psychology and biology at Ashoka University in Sonipat, India, who was not involved in the work. . “By showing that a simple behavioral change can help reverse sleep disturbances seen in mutant Kismet flies, this study offers a way to break this cycle.”
Sleep restriction therapy is not standardized or uniformly applied for insomnia, making it difficult to assess its therapeutic effectiveness at this point, Gould cautions. However, “research is underway to try to identify the best approaches for this therapy,” she says.
Future research should study how CHD8 mutations can affect melatonin, a molecule that is integral to sleep, says Gould. Previous work has found that melatonin supplements can help children with autism fall asleep faster and stay asleep longer.
Additionally, scientists could explore whether Kismet mutations also cause cognitive problems in fruit flies, and whether sleep restriction therapy might help alleviate some of these issues as well, Melnattur explains.
“We also want to understand what CHD8, CHD7 and Kismet do in the glia and the blood-brain barrier of humans and flies,” says Barber. “From there, we can then explore potential pharmacological therapies, as opposed to simple behavioral interventions. “
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