Sleep issues in autism might stem from leaky mind barrier | Spectrum
Sleep cells: The genes CHD7 and CHD8 associated with autism are strongly expressed in glia (pink and blue, left column) (yellow, middle and right column)
According to a new study on fruit flies, the sleep disorders that some autistic people have may be due in part to leaks in the barrier that protects the brain from toxins or pathogens in the blood.
The work also suggests that behavioral treatment for chronic insomnia could help alleviate sleep problems in some autistic people.
“Sleep restriction therapy is a first-line treatment for insomnia, but it is rarely used in the clinic for genetic syndromes or neurodevelopmental disorders,” says study director Annette Schenck, professor of translational genomics of neurodevelopmental disorders at the Radboud University Medical Center in Nijmegen , Netherlands. “We are confident that this 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 causes of these problems, the researchers used data from 27 people with mutations in CHD7 or CHD8, two closely related genes strongly linked to autism and sleep problems.
The data comes from a sleep clinic, the Simons Simplex Collection, a collection of genetic and trait information from families with an autistic child, and a University of Washington study entitled The Investigation of Genetic Exome Research. (The Simons Simplex Collection is funded by the Simons Foundation, Spectrum’s parent organization.)
Autistic people with mutations in CHD7 or CHD8 had significantly more difficulty falling asleep and staying asleep than about 2,300 autistic control subjects without known autism-related mutations, the study shows. And three people with CHD7 mutations and one person with a CHD8 mutation had chronic insomnia.
Glial surprise:
Next, researchers 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 humans with CHD7 or CHD8 mutations. Suppression of kismet expression only in neurons did not cause sleep problems, the researchers found, but suppression in neuron-supporting glial cells during the development of the flies did.
“Glia is really overlooked – they are the sad, neglected stepchildren of the brain,” says Annika Barber, an assistant professor of molecular biology and biochemistry at Rutgers University in New Jersey who was not involved in the study. “This work throws a fascinating spotlight on a group [of cells] not often thought about neurological development disorders. “
The flies’ sleep problems have been specifically linked to subperineurial glial cells, a group of about 300 cells that help build the insect’s blood-brain barrier.
“These cells have not yet been reported as the cause of sleep fragmentation,” says Schenck. “Instead, it is known that sleep loss affects the functioning of the blood-brain barrier in certain neurological diseases. Obviously, sleep and the regulation of the blood-brain barrier are closely intertwined, and so far we only know half the story. “
Further experiments showed that levels of the neurotransmitter dopamine, which is important for sleep and wakefulness, were unchanged in the flies lacking kismet in glia. But these flies had abnormally high levels of another neurotransmitter, serotonin, as they developed.
Using a drug to suppress serotonin levels in the flies during development eased their sleep disorders. The rise in serotonin levels in wild-type flies during development led to sleep problems in adulthood. The results were published in Science Advances in June.
A condition called hyperserotonaemia, which is characterized by increased levels of serotonin, is often associated with autism, although it remains unclear why. The new findings could renew interest in the role of serotonin in autism, especially how it can cross the blood-brain barrier, says Georgianna Gould, associate professor of cellular and integrative physiology at the University of Texas Health Science Center at San Antonio did not take part in this work.
Mutations that turn off either CHD7 or CHD8 are extremely rare, but “they can be representative of more common blood-brain barrier deficiencies due to several other causes,” adds Gould.
Simple intervention:
In a final round of experiments, the researchers developed an insect version of sleep restriction therapy that first limits the darkness of the insects and then gradually increases it.
Controlling darkness and light in this way helped solve the model flies’ sleeping problems, the team found.
The sleep disorders of autistic people can worsen cognitive problems and lead to further sleep disorders, says Krishna Melnattur, an assistant professor of psychology and biology at Ashoka University in Sonipat, India, who was not involved in the work. “By showing that a simple change in behavior can help reverse the sleep disorders seen in kismet mutant flies, this study offers a way to break that cycle.”
Sleep restriction therapy is not standardized or applied consistently for insomnia, making it difficult to assess its therapeutic effectiveness at this stage, warns Gould. “However, there is ongoing research trying to find the best approaches for this therapy,” she says.
Future research should investigate how CHD8 mutations can affect melatonin, a molecule important for sleep, says Gould. Previous work found that melatonin supplements could help children with autism fall asleep faster and stay asleep longer.
In addition, scientists could investigate whether kismet mutations also lead to cognitive problems in fruit flies, and whether sleep restriction therapy could also help alleviate some of these problems, Melnattur says.
“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 research potential pharmacological therapies, as opposed to behavioral interventions.”
