An active Unc13A is Reboundless in sleep homeostasis

One of the major characteristics of sleep is homeostatic sleep rebound following sleep loss. While the molecular mechanisms of baseline sleep regulation have been intensively studied, a specific molecular understanding of sleep rebound remains elusive. Here, we show that a constitutively active form of the Munc13-family presynaptic release factor Unc13A, which lacks the inhibitory Ca²⁺/calmodulin interaction domain (Unc13A^WRWR), dominantly suppressed sleep rebound upon acute sleep deprivation, leading to a nearly complete elimination of recovery sleep (“reboundless”). In contrast, baseline sleep remained largely normal. Through a genetic modifier screen, we found that this dominant “reboundless” phenotype of Unc13A^WRWRwas rescued by a partial loss of αSnap, a cofactor of NSF required for disassembly and recycling of post-fusioncis-SNARE complex. Given that Unc13A promotes fusion-competenttrans-SNARE complex formation, these findings suggest that sleep rebound may depend on a delicate balance between SNARE complex assembly and recycling. Additionally, we found that expression of a human disease-associated active Unc13A (Unc13A^PL) variant attenuated baseline and rebound sleep. Since both Unc13A^WRWRand Unc13A^PLwere shown to promote presynaptic release probability (P_r), we speculate that Unc13A suppresses recovery sleep likely by increasing P_rand subsequently enhancing synaptic transmission, probably through elevatedtrans-SNARE formation and efficientcis-SNARE recycling. Taken together, our data demonstrate a fundamental role of Unc13A and SNARE dynamics in sleep homeostasis.