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.

Vulnerability to drug addiction relies on substantial individual differences. We previously demonstrated that serotonin transporter knockout (SERT−/−) rats show increased cocaine intake and develop signs of compulsivity. However, the underlying neural mechanisms are not fully understood. Given the pivotal role of glutamate and prefrontal cortex in cocaine‐seeking behavior, we sought to investigate the expression of proteins implicated in glutamate neurotransmission in the prefrontal cortex of naïve and cocaine‐exposed rats lacking SERT. We focused on the infralimbic (ILc) and prelimbic (PLc) cortices, which are theorized to exert opposing effects on the control over subcortical brain areas. SERT−/− rats, which compared to wild‐type (SERT+/+) rats show increased ShA and LgA intake short‐access (ShA) and long‐access (LgA) cocaine intake, were sacrificed 24 h into withdrawal for ex vivo molecular analyses. In the ILc homogenate of SERT−/− rats, we observed a sharp increase in glial glutamate transporter 1 (GLT‐1) after ShA, but not LgA, cocaine intake. This was paralleled by ShA‐induced increases in GluN1, GluN2A, and GluN2B NMDA receptor subunits and their scaffolding protein SAP102 in the ILc homogenate, but not postsynaptic density, of these knockout animals. In the PLc, we found no major changes in the homogenate; conversely, the expression of GluN1 and GluN2A NMDA receptor subunits was increased in the postsynaptic density under ShA conditions and reduced under LgA conditions. These results point to SERT as a critical regulator of glutamate homeostasis in a way that differs between the subregions investigated, the duration of cocaine exposure as well as the cellular compartment analyzed.

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Habituation, the most ancient and fundamental form of learning, manifests already before birth. Neuroscientists have been fascinated for decades by its function as a firewall protecting our brains from sensory information overload and its indispensability for higher cognitive processing. Evidence that habituation learning is affected in autism and related monogenic neurodevelopmental syndromes and their animal models has exponentially grown, but the potential of this convergence to advance both fields is still largely unexploited.In this review, we provide a systematic overview of the genes that to date have been demonstrated to underlie habituation across species. We describe the biological processes they converge on, and highlight core regulatory pathways and repurposable drugs that may alleviate the habituation deficits associated with their dysregulation. We also summarize currently used habituation paradigms and extract the most important arguments from literature that support the crucial role of habituation for cognition in health and disease. We conclude that habituation is a powerful tool to overcome current bottlenecks in research, diagnostics and treatment of neurodevelopmental disorders.

Habituation is the most ancient and fundamental form of learning. As a firewall that protects our brain from sensory overload, it is indispensable for higher cognitive processes. Studies in humans and animal models provide a growing body of evidence that habituation is affected in autism and related monogenic neurodevelopmental disorders (NDDs). An integrated application of habituation assessment in NDDs and their animal models has currently unexploited potential for fundamental neuroscience and medical care.With the aim to gain mechanistic insights, we systematically retrieved genes that have been demonstrated in the literature to underlie habituation. We identified 258 evolutionarily conserved genes across species, describe the biological processes they converge on, and highlight regulatory pathways and drugs that may alleviate the habituation deficits associated with their dysregulation. We also summarize current habituation paradigms and extract the most decisive arguments from the literature that support the crucial role of habituation for cognition in health and disease. We conclude that habituation is a conserved, quantitative, cognition- and disease-relevant process that can connect preclinical and clinical work, and hence is a powerful tool to advance research, diagnostics,’’ and treatment of NDDs.