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bioRxiv · 10.1101/2024.09.25.615048

Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2

Mace, K.·Zimmerman, A. J.·Chesi, A.·Doldur-Balli, F.·Kim, H.·Almeraya Del Valle, E.·Pack, A. I.·Grant, S. F.·Kayser, M. S.
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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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Mace, K., Zimmerman, A. J., Chesi, A., Doldur-Balli, F., Kim, H., Almeraya Del Valle, E., Pack, A. I., Grant, S. F., Kayser, M. S.. 2024-09-26. Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2. https://doi.org/10.1101/2024.09.25.615048

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