During sleep, animals exhibit a heightened arousal threshold and decreased behavioral response to external stimuli. The molecular and cellular mechanisms underlying these changes are not fully understood. We report here that the activity of the C. elegans NALCN sodium leak channel, NCA, is critical for normal sleep and arousal. Sodium leak channels regulate resting membrane potential, thus contributing to the overall neuronal excitability (PMID:17448995, PMID:23522043). We found that diminished NCA activity in C. elegans robustly increased arousal threshold during sleep bouts in L4-to-adult lethargus, consistent with decreased excitability. Quantity of sleep was only modestly increased in these animals, whereas heightened NCA activity dramatically decreased sleep. Loss of cGMP-dependent protein kinase EGL-4 suppressed NCA loss of function defects. This suggests a model in which increased arousal threshold during sleep requires down-regulation of the sodium leak channel, which, directly or indirectly, activates the EGL-4 protein kinase. Others have suggested that Drosophila sodium leak channel drives the pigment dispersing factor (PDF) neuropeptide release, regulating daily rhythmic behavior (PMID:16364900, PMID:20362452). However, in C. elegans, losing PDF-1, one of the two PDF neuropeptides, had no impact on animals with increased NCA function. Intriguingly, loss of the PDF receptor increased arousal threshold, reminiscent of decreased NCA function.
NCA channels, cooperatively with gap junctions, are required for normal response to general anesthetics (PMID:3576211) and function in the premotor interneurons to regulate neuronal excitability (PMID:25716181, PMID: 21489288). Consistent with these findings, loss of UNC-7 or UNC-9 gap junction proteins partially suppressed the increased sleep of animals with diminished NCA function. Moreover, loss of UNC-7 in premotor interneurons or loss of UNC-9 in motor neurons significantly decreased sleep and lowered arousal threshold during sleep. Conversely, overexpressing UNC-7 and UNC-9 in adult animals was sufficient to induce anachronistic sleep. Combined, these results emphasize the conservation and importance of neuronal activity during sleep, demonstrate a role for gap junctions in sleep, and identify possible targets for the modulation of sleep entry and maintenance.
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