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<p>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 <i>beat-Ia/CADM2</i>, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of <i>Drosophila beat-Ia</i> results in sleepy flies and loss of the vertebrate ortholog of <i>beat-Ia</i>, <i>CADM2</i>, results in sleepy fish. We delineate a developmental function for <i>beat-Ia</i> 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 <i>Drosophila</i> homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lacking <i>CADM2</i>. These findings point towards NPY modulation as a treatment target for human hypersomnia.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • Kyla Mace,
  • Amber Zimmerman,
  • Alessandra Chesi,
  • Fusun Doldur-Balli,
  • Hayle Kim,
  • Erika Almeraya del Valle,
  • Jeffrey B. Rosa,
  • Allan I. Pack,
  • Struan F. A. Grant,
  • Matthew S. Kayser

摘要

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.