Abstract
Idiopathic hypersomnia (IH) is a poorly understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish and flies, we uncover a role for beat-Ia/CADM2, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of Drosophila beat-Ia results in sleepy flies and loss of the vertebrate ortholog of beat-Ia, CADM2, results in sleepy fish. We delineate a developmental function for beat-Ia in synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain. Brain connectome and experimental evidence demonstrate these NPF outputs synapse onto a subpopulation of SEZ GABAergic neurons to stabilize arousal. NPF is the Drosophila homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lacking CADM2. These findings point towards NPY modulation as a treatment target for human hypersomnia.
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Acknowledgements
We thank David Raizen, Amita Sehgal, members of the Kayser Lab, members of the Raizen Lab, and members of the Penn Chronobiology and Sleep Institute for helpful discussions and input. NIH T32GM008076 (K.M.). NIH T32HL007953 (KM). NIH T32HL007713 (A.Z.). NIH R35HG011959 (A.C.). Fulbright Visiting Scholar Program—Postdoctoral Grant (FY-2017-TR-PD-07) (FDB). NIH P01HL160471 (A.I.P.). NIH R01HL143790 (S.F.G.). Daniel B. Burke Endowed Chair for Diabetes Research (S.F.A.G.). NIH DP2NS111996 (MSK). NIH R01NS120979 (M.S.K.). NIH R35NS137329 (M.S.K.). Linda Pechenik Montague Award (M.S.K.). Burroughs Wellcome Career Award for Medical Scientists (M.S.K.).
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Conceptualization: K.M., A.Z., A.C., A.I.P., S.F.A.G., M.S.K. Investigation: K.M., A.Z., A.C., F.D.B., H.K., E.A.D.V., J.R. Writing—Original Draft: K.M., M.S.K. Writing—Review and Editing: K.M., A.Z., A.C., F.D.B., H.K., E.A.D.V., J.R., A.I.P., S.F.A.G., M.S.K. Project Supervision and Funding: M.S.K.
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Mace, K., Zimmerman, A., Chesi, A. et al. Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68343-1
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DOI: https://doi.org/10.1038/s41467-026-68343-1
