SIK3 links synaptic strength to sleep pressure through RhoA signaling

Sleep is regulated by homeostatic sleep pressure, which accumulates during wakefulness and diminishes during sleep, leading to wakefulness. Recent studies suggest that synaptic potentiation reflects sleep pressure; however, the specific intracellular mechanisms connecting synaptic strength to sleep pressure are not well understood. In this study, researchers discovered that the sleep-promoting kinase SIK3 connects synaptic strength and sleep pressure through RhoA signaling.

SIK3 is essential for dendritic spine growth, triggered by chemical long-term potentiation (cLTP) in cultured cortical pyramidal neurons. Additionally, SIK3 positively regulates spine size in the prefrontal cortex in living organisms. cLTP reduced RhoA activity in an SIK3-dependent manner during spine enlargement, while activating RhoA decreased EEG delta density during non-rapid eye movement sleep (NREM sleep), a sign of sleep pressure.

Identifying several RhoA regulators through SIK3 substrate screening, the team found that phosphorylation by SIK3 activates GEF-H1. Interestingly, contrary to expectations, RhoA stimulation via pharmacological activation of GEF-H1 enlarged spine size in cultured neurons, and expressing constitutively active GEF-H1 increased NREM sleep delta density in a RhoA-dependent manner.

In summary, these findings reveal that SIK3 enlarges spine size and boosts NREM sleep delta density through two RhoA-dependent pathways, generating conflicting intermediate outcomes. The study identifies two conflicting SIK3-RhoA signaling pathways that link synaptic regulation to sleep homeostasis.