Propofol inhibits norepinephrine release in vivo at presynaptic varicosities of locus coeruleus neurones in zebrafish larvae by Wenjie Du & Yue Hu & Yongxin Yang & Jia Li & Mingjian Liu & Changmei Zhang & Yufan Wang & Peishan Xiang & Qiong Yu & Jiulin Du & Yingwei Wang instant download

Propofol inhibits norepinephrine release in vivo at presynaptic varicosities of locus coeruleus neurones in zebrafish larvae by Wenjie Du & Yue Hu & Yongxin Yang & Jia Li & Mingjian Liu & Changmei Zhang & Yufan Wang & Peishan Xiang & Qiong Yu & Jiulin Du & Yingwei Wang instant download

AbstractBackground: Understanding the mechanisms by which general anaesthetics induce loss of consciousness remains one ofthe important scientific challenges in medicine and neuroscience. The locus coeruleus-norepinephrine (LC-NE) systemplays important roles in general anaesthesia. Both i.v. and inhalation anaesthetics can reduce NE signalling by suppressing the excitatory synaptic inputs and intrinsic excitability of LC-NE neurones. However, it remains unknownwhether anaesthetics can directly target presynaptic sites on LC-NE neurone axons to impair NE release.Methods: In vivo whole-cell recording and chemogenetics were used to control the activity of LC-NE neurones in intactlarval zebrafish, while in vivo time-lapse imaging was used to examine NE release and Ca2+ influx at individual presynaptic varicosities of the recorded neurones. The G protein-coupled receptor (GPCR) activation-based NE sensorGRABNE2m and the genetically encoded Ca2+ sensor GCaMP6s were used to detect NE release and Ca2+ levels, respectively.Results: Propofol directly inhibited NE release from individual presynaptic varicosities of LC-NE neurones, becauseGRABNE2m signals induced by precisely controlled activity of LC-NE neurones were markedly reduced after propofolapplication. Propofol significantly suppressed presynaptic varicosity Ca2+ activities of LC-NE neurones. These effectswere diminished by co-application of picrotoxin, an antagonist of gamma-aminobutyric acid type A receptors, to the areawhere the varicosities are located. The degree of propofol-induced inhibition varied across individual varicosities but wasrelatively homogeneous among different brain areas.Conclusions: Propofol can directly target the locus coeruleus norepinephrine neurone axons to suppress norepinephrinerelease at presynaptic varicosities.Keywords: Ca2+ activity; GABAA receptor; locus coeruleus; norepinephrine release; presynaptic varic