SIK3-HDAC4 in the brain’s internal clock controls waking time at nightfall and daily rhythm length in mice

Salt-inducible kinase 3 (SIK3) deficiency in specific neurons lengthened the behavioral circadian cycle in laboratory mice.

• Deficiency of SIK3 in GABAergic or neuromedin S-producing neurons delayed the peak of arousal without affecting daily sleep amounts.
• A gain-of-function mutation in GABAergic neurons resulted in earlier activity onset and a shorter circadian period.
• Loss of SIK3 in arginine vasopressin-producing neurons also lengthened the circadian cycle, but did not change the timing of arousal.
• Heterozygous deficiency of histone deacetylase 4 (HDAC4) shortened the circadian cycle, while a mutant resistant to SIK3 phosphorylation delayed arousal timing.
• Phase-delayed expressions of core clock genes were observed in the liver of mice lacking SIK3 in GABAergic neurons.

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