The CHD8/CHD7/Kismet family links blood-brain barrier glia and serotonin to ASD-associated sleep defects

Abstract

Sleep disturbances in autism and neurodevelopmental disorders are common and adversely affect patient’s quality of life, yet the underlying mechanisms are understudied. 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. This role localizes to subperineurial glia constituting the blood-brain barrier. We demonstrate that Kismet-related sleep disturbances are caused by high serotonin during development, paralleling a well-established but genetically unsolved autism endophenotype. Despite their developmental origin, Kismet’s sleep architecture defects can be reversed in adulthood by a behavioral regime resembling human sleep restriction therapy. Our findings provide fundamental insights into glial regulation of sleep and propose a causal mechanistic link between the CHD8/CHD7/Kismet family, developmental hyperserotonemia, and autism-associated sleep disturbances.

Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance

“…Moreover, people with IBD who experience constipation often have lower plasmatic levels of serotonin ( Atkinson et al, 2006 ). Recent work using Drosophila melanogaster indicates that the loss of CHD8 / CHD7 ortholog, kismet , leads to increased levels of serotonin in the brain and in the proventriculus and the anterior midgut, which can be zebrafish equivalents of the intestinal bulb and the anterior part of the mid-intestine, respectively ( Coll-Tané et al, 2021 ). Our work is in contradiction with this study regarding observed levels of serotonin in the mid-intestine.…”

Mutation of the Drosophila melanogaster serotonin transporter dSERT impacts sleep, courtship, and feeding behaviors

“…Serotonin has been previously shown to affect development in both mammals (80,81) and D. melanogaster [82][83][84][85][86][87][88][89][90][91]. Interestingly, patients with mutations in the autism risk gene CHD8 show defects in sleep initiation and maintenance, and mutation of the D. melanogaster ortholog kismet disrupts sleep architecture and increases serotonin labeling of the gut during development [92]. The hyper serotonergic state observed during development appear to decrease rather than increase sleep [92] in contrast to most of the reported effects of serotonin in the adult fly.…”

Decoding microRNAs in autism spectrum disorder

“…Among them, miR-1224-5p, miR-292a-5p, miR-760-3p, miR-331-3p, miR-874-3p, miR-134-5p, miR-154-3p, miR-495-3p, miR-376b-3p, and miR-299a-3p were down-regulated, whereas miR-21c, miR-135a-5p, and miR-16-5p were up-regulated. 76 Intriguingly, all these miRNAs were predicted to target ASD-linked genes, such as CHD7 77 and CLCN3 , 78 which are related to neuronal development and neuron adhesion, respectively ( Figure 2 ).…”