Cross-species evidence implicates synaptic adhesion molecules beat-Ia/CADM2 in excessive sleepiness through a developmental function in neuropeptide F neurite elaboration, with NPY receptor agonism restoring normal sleep in zebrafish lacking CADM2.
Neuronal knockdown of Drosophila beat-Ia results in increased sleep (sleepy flies).
Loss of CADM2, the vertebrate ortholog of beat-Ia, results in increased sleep in zebrafish.
beat-Ia has a developmental function in synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain.
NPF outputs in the SEZ synapse onto a subpopulation of GABAergic neurons that function to stabilize arousal.
An NPY receptor agonist restores sleep to normal levels in zebrafish lacking CADM2.
Human genomics data were combined with cross-species functional studies to implicate beat-Ia/CADM2 in idiopathic hypersomnia.
This research suggests that a protein called beat-Ia in fruit flies and its equivalent in vertebrates, CADM2, plays an important role in controlling how sleepy animals are during their active periods. When scientists removed or reduced this protein in the neurons of fruit flies, the flies slept too much — similar to people with idiopathic hypersomnia, a poorly understood condition where people feel excessively sleepy even after a full night of sleep. The same result was found in zebrafish that lacked CADM2, showing that this sleep-regulating function is preserved across very different species. The researchers traced the cause to early brain development: beat-Ia is needed to properly wire up brain circuits involving a chemical messenger called neuropeptide F (NPF), which is closely related to a human brain chemical called neuropeptide Y (NPY). Without beat-Ia, the nerve fibers that release NPF don't form their connections properly in a key brain region, which in turn disrupts a group of calming (GABAergic) neurons that normally help keep animals awake and alert. This points to a developmental origin for the excessive sleepiness — the problem starts when the brain is being built, not just when it's functioning in adulthood. Importantly, when the researchers gave zebrafish without CADM2 a drug that activates NPY receptors, their sleep returned to normal levels. This suggests that NPY-based treatments might one day help people with idiopathic hypersomnia, a condition that currently has very limited treatment options. The study's strength comes from its use of multiple species and approaches — human genetics, fly behavior, zebrafish pharmacology, and brain circuit mapping — all pointing to the same biological pathway.
Mace K, Zimmerman A, Chesi A, Doldur-Balli F, Kim H, Almeraya Del Valle E, et al.. (2026). Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2.. Nature communications. https://doi.org/10.1038/s41467-026-68343-1