组成性激活的突触前释放因子 Unc13A 阻止果蝇的睡眠稳态反弹

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 Ca 2+ /calmodulin interaction domain (Unc13A WRWR ), dominantly suppressed homeostatic sleep rebound following acute sleep deprivation, leading to a near-complete elimination of recovery sleep ("Reboundless"). In contrast, baseline sleep remained largely normal. Through a genetic modifier screen, we identified partial loss of αSnap, a cofactor of N-ethylmaleimide-sensitive factor (NSF) required for disassembly and recycling of post-fusion cis-SNARE complex, as a potent suppressor of the reboundless phenotype of Unc13A WRWR . Given that Unc13A promotes the formation of the fusion-competent trans-SNARE complex, these findings implicate that sleep rebound critically depends on a delicate balance between SNARE complex assembly and recycling. Since Unc13A WRWR has been shown to promote presynaptic release probability (P r ), we speculate that active Unc13A suppresses rebound sleep likely by increasing P r and subsequently enhancing synaptic transmission. Consistently, an elevated dependence on trans-SNARE formation and cis-SNARE recycling seems to explain the functional and behavioral phenotypes of Unc13A WRWR . Taken together, our data suggest a fundamental role of P r mediated by Unc13A and SNARE dynamics in sleep homeostasis.