Summary: Research using fruit fly models of autism links sleep disruption to elevated serotonin levels, tracing the increase to glial cells that form the blood-brain barrier.
Source: Radboud University
Poor sleep undermines health, concentration, memory, and stress resilience. Sleep problems are common in people with neurodevelopmental conditions such as autism spectrum disorder (ASD) and intellectual disability, yet the mechanisms behind these disturbances remain poorly understood.
A multinational Dutch–American team led by researchers at Radboudumc reports new insights in Science Advances into how genetic causes of autism can produce sleep disruption. By modeling two autism-associated gene defects in Drosophila (fruit flies), the team found sleep fragmentation comparable to that seen in affected patients and identified elevated serotonin as a key factor.
Crucially, the researchers traced the source of increased serotonin to glial cells that form the blood-brain barrier in flies, revealing a previously unrecognized glial contribution to sleep defects linked to autism-related genes and suggesting potential routes for intervention.
Sleep disturbance broadly reduces quality of life; families of people with autism commonly report that fragmented sleep—difficulty falling and staying asleep, frequent night awakenings and poor sleep continuity—is one of the most debilitating daily challenges. Despite this, the biological drivers of these sleep problems have received limited attention.
The team, coordinated by professor Annette Schenck in collaboration with professor Tjitske Kleefstra at Radboudumc, combined clinical observations with experiments in fruit flies to investigate sleep phenotypes associated with mutations in CHD8 and CHD7, two genes strongly implicated in autism and related syndromes.
Schenck explains: “We examined sleep in patients with CHD8 or CHD7 mutations and found a consistent pattern of sleep fragmentation—falling asleep is difficult, and nights are frequently interrupted. These traits are also present in autism more broadly, but particularly pronounced in individuals with CHD8 or CHD7 mutations, which inspired us to explore the mechanisms behind these symptoms.”
From patients to flies
Fruit flies offer powerful genetic tools and conservation of many biological pathways. In Drosophila, a single gene called kismet is the ortholog of human CHD8 and CHD7. Mutations in kismet can therefore model aspects of CHD8/CHD7 dysfunction in a tractable organism.
Lead author Mireia Coll-Tané reports: “Flies carrying kismet mutations exhibit pronounced sleep fragmentation, waking repeatedly during the night—mirroring the sleep pattern we documented in patients with CHD8 or CHD7 mutations.”
Glial cells, not neurons, drive the defect
Schenck’s lab specializes in modeling neurodevelopmental disease genes in Drosophila and assessing behavior and neural function. When the team confirmed sleep fragmentation in kismet mutant flies, they used the model to localize the source of the problem.
Surprisingly, the effect did not arise from neurons—the cells normally emphasized in behavior studies—but from glial cells. Coll-Tané explains: “Kismet function during development in a small population of roughly 300 glial cells that form the fly’s blood-brain barrier is essential for normal adult sleep. Disruption of kismet in these barrier-forming glia produces the sleep fragmentation.”
Serotonin elevation links gene defects to sleep fragmentation
Although dopamine often contributes to sleep regulation, the researchers found dopamine levels were unchanged in kismet mutants. Instead, serotonin emerged as the critical neurotransmitter. Reducing kismet specifically in glia doubled serotonin levels in fly heads—a form of developmental hyperserotonemia that parallels a well-known biomarker observed in many people with autism.
A combination of genetic manipulations and pharmacological experiments provided evidence that elevated serotonin during development is responsible for the sleep fragmentation associated with kismet loss. Coll-Tané notes: “We link a major genetic risk factor for autism to a frequently observed biomarker—hyperserotonemia—and to a clinically meaningful sleep problem.”
Therapeutic implications
A critical question is whether sleep disturbances rooted in developmental processes can be improved in adults. Any viable treatment should be non-invasive and safe. The team tested a behavioral approach: sleep restriction therapy (SRT) adapted for flies. This method—analogous to a human insomnia intervention—uses a controlled light schedule to limit time in bed.
Schenck reports the behavioral regime successfully restored consolidated sleep in adult flies despite the developmental origin of the problem. “A simple light schedule mimicking shorter nights improved sleep and reversed fragmentation. This suggests that behavioral interventions may have therapeutic value even when sleep defects arise from early developmental changes,” she says.
Next steps in humans
The findings motivate clinical follow-up. Kleefstra adds: “We have documented CHD7 and CHD8 expression in the human blood-brain barrier during development and adulthood. Our next steps are to collect clinical sleep data from affected individuals and to pilot sleep restriction therapy in collaboration with clinical sleep experts. We will continue applying a human-to-fly-and-back strategy to other disorders as well.”
This study opens new avenues for understanding how glial biology and developmental changes in serotonin can shape sleep in autism and related neurodevelopmental conditions, and it highlights behavioral strategies that could be translated into clinical practice.
About this autism research news
Source: Radboud University
Contact: Pieter Lomans – Radboud University
Image: The image is in the public domain
Original Research: Open access.
“The CHD8/CHD7/Kismet family links blood-brain barrier glia and serotonin to ASD-associated sleep defects” by Mireia Coll-Tané et al. Science Advances
Abstract
The CHD8/CHD7/Kismet family links blood-brain barrier glia and serotonin to ASD-associated sleep defects
Sleep disturbances in autism spectrum disorder and other neurodevelopmental conditions are common and diminish patient quality of life, yet their biological basis remains understudied.
We report that individuals with mutations in CHD8 or CHD7—two high-confidence autism risk genes—exhibit impaired sleep maintenance. These sleep defects are recapitulated in Drosophila mutants of kismet, the single fly ortholog of CHD8/CHD7.
Kismet function in glia is required for normal sleep architecture during development and in adulthood. This requirement maps specifically to subperineurial glia that form the blood-brain barrier. We show that elevated serotonin during development drives Kismet-related sleep fragmentation, paralleling the hyperserotonemia observed in many individuals with autism. Despite their developmental origin, these sleep architecture defects can be ameliorated in adulthood by a behavioral sleep-restriction regime.
These results provide mechanistic insight into glial regulation of sleep and propose a causal link between the CHD8/CHD7/Kismet gene family, developmental hyperserotonemia, and autism-associated sleep disturbances.