Regular poor sleep puts us at risk for serious medical conditions, including obesity, heart disease, and diabetes, and it can shorten life expectancy. It also affects our ability to concentrate and memorize. Those with neurodevelopmental disorders such as autism and intellectual disability, frequently suffer from sleep problems. However, their underlying mechanisms remain unclear. Now, a new study using a fruit fly model, demonstrates that poor sleep in neurodevelopmental disorders may be caused by high levels of serotonin. Researchers also discovered that the origin of high serotonin and sleep issues are linked to the blood-brain barrier.
The new study, titled “The CHD8/CHD7/Kismet family links blood-brain barrier glia and serotonin to ASD-associated sleep defects,” is published in the journal Science Advances, and led by researchers at Radboudumc University Medical Center.
“Sleep disturbances in autism and neurodevelopmental disorders are common and adversely affect patient’s quality of life, yet the underlying mechanisms are understudied,” wrote the researchers. “We found that individuals with mutations in CHD8, among the highest-confidence autism risk genes, or CHD7 suffer from disturbed sleep maintenance. These defects are recapitulated in Drosophila mutants affecting kismet, the sole CHD8/CHD7 ortholog. We show that kismet is required in glia for early developmental and adult sleep architecture.”
“We first looked very closely at the sleep problems in two specific patient groups with neurodevelopmental disorders,” explained Annette Schenck, PhD, professor at Radboudumc. “They have mutations in the CHD8 gene, a leading genetic cause of autism, or in a closely related gene, CHD7, giving raise to CHARGE syndrome.
“We see that the bad sleep in these disorders particularly comes from problems falling and staying asleep, which causes night awakenings and low sleep quality. We call this problem sleep fragmentation. It is frequent in autism in general, but even more frequent in individuals with mutations in CHD8 or CHD7. According to affected families, these sleep problems are one of their biggest problems in daily life management. This motivated us to study sleep disturbances, in context of these genes and disorders further.”
In the fruit fly, CHD8 and CHD7 are represented by a single gene called kismet. The researchers used fruit flies, as mutations in kismet in the fruit fly can mimic genes in humans. Mireia Coll-Tané, a researcher in Schenck’s group and lead author of the study added, “We see that flies with mutations in kismet have problems staying asleep, waking up during night extremely frequently. They show the same characteristics that we see in people with mutations in CHD8 and CHD7.”
When the researchers discovered sleep disturbance to be present in flies, they knew their model would help them find the origin of the disturbance. The researchers observed that kismet is important for good sleep for adult flies. However it is also important during development, and that the adult sleep defects result from decreased kismet during the developmental period.
“We also found that kismet was not important in the neurons, the cells that are classically seen to regulate behavior, but in the other main cell type present in the brain: the glial cells,” noted Coll-Tané. “Glia have many important functions, such as supporting neurons, cleaning up waste, and contributing to the blood-brain barrier. We saw that kismet is important, already in early development, in a group of only 300 glial cells that form the blood-brain barrier in the fly. They are the origin of the sleep fragmentation.”
The neurotransmitter dopamine has been linked to sleep issues. However, in this study dopamine levels were normal. To their surprise, researchers observed the neurotransmitter serotonin appeared to play a critical role.
“When we reduce kismet specifically in glia, we found the concentration of serotonin in fruit fly heads to be doubled,” stated Coll-Tané. “This is a very interesting finding because increased serotonin, also referred to as hyperserotonemia, is one of the most commonly found biomarkers in autism.”
Further research is needed before it is studied in humans. “We have already shown in our article that CHD7 and CHD8 are expressed in the human blood-brain barrier, both during development and adulthood,” said Tjitske Kleefstra, a clinical geneticist at Radboudumc University Medical Center. “Now we aim to collect further clinical data and apply SRT to these patients, in close collaboration with the expert sleep clinic Kempenhaeghe in Heeze. Together, we are expanding our ‘human-to-fruit-fly-and-back’ strategy to a number of other disorders.”