Characterize The Molecular And Cellular Mechanisms Of Neurexin In Sleep Regulation In Drosophila

Sleep is an essential and evolutionarily conserved behavior,but also remains one of the least understood biological phenomena.Sleep disorders are common,and are also frequently observed in the children with autism spectrum disorders(ASDs).However,the cause of those sleep disturbances is largely unknown.Clinical studies and genetic association analyses reveal that mutations in neurexin genes are strongly linked to ASDs.Neurexins are synaptic adhesion molecules closely involved in synaptic formation and synaptic transmission.Although a recent report provided some knowledge about the interactions between neurexin-mediated synaptic plasticity and sleep regulation,the potential roles and underlying molecular and neuroanatomical mechanisms of neurexin-mediated synaptic transmission in sleep regulation are worth further investigation.Here,using Drosophila as a model,with the combination of the approaches in genetics,biochemistry and molecular biology,behavioral study,and imaging,we investigated the molecular and cellular mechanisms of neurexin in sleep regulation.First,we show that lack of the Drosophila a-neurexin homolog significantly reduces the quantity and quality of nighttime sleep and impairs sleep homeostasis.We report that neurexin expression in Drosophila mushroom body(MB)?/? neurons is essential for nighttime sleep,and further demonstrate that MB ?/? surface(?/?s)neuron-expressed neurexin controls sleep during the whole night,whereas MB ?/? core(?/?c)neuron-derived neurexin only promotes mid-night(ZT14-ZT21)sleep.To exclude the potential roles of neurexin mutations in neural development,we acutely depleted neurexin expression in adult Drosophila,and recaptured the reduced nighttime sleep.Based on these results,we further reveal that defective sleep in neurexin mutants is due to impaired MB ?/? neuronal output,and show that neurexin functionally couples calcium channels(Cac)to regulate synaptic transmission.Finally,we determine that MB ?/?s neurons release both acetylcholine and short neuropeptide F(sNPF)to promote nighttime sleep,whereas MB ?/?c neurons release sNPF to promote mid-night(ZT14-ZT21)sleep.Our findings reveal that neurexin functionally couples calcium channels(Cac)to regulate nighttime sleep by mediating the synaptic transmission of MB ?/? neurons,and different populations of MB ?/?p neurons are involved in various phases of nighttime sleep.This study elucidates roles of synaptic transmission in sleep regulation,reveals relationships between autism-related genes and sleep,and might offer insights into the mechanisms of sleep disturbances and autism disorders.