Transitional Role Of Spontaneous Cholinergic Network Activity To Glutamatergic Network Activity In Ketamine-induced Neuronal Apoptosis During The Early Development Of Rat Retina

Mounting evidence shows that general anesthetics can cause widespread neuronal apoptosis in the central nervous system of developmental animals.Recent studies have showed that deprivation of neuronal rhythmic spontaneous electrical activities during early developmental period,especially in the peak period of synaptogenesis,may contribute to general anesthetics-induced neuronal apoptosis.However,it’s mechanism still unclear.In this study,we combined the patch clamp electrophysiological recording,immunohistochemistry and TUNEL assay to investigate the possible mechanism of neuronal rhythmic spontaneous electrical activities in ketamine induced neuronal apoptosis and potential treatment stratagy.We found that the transition period of spontaneous cholinergic network activity to glutamatergic network activity coincide with peak season of neuronal apoptosis induced by ketamine,which occurs in postnatal 7-9 day(P7-P9);The neuronal rhythmic spontaneous electrical activities could be blocked and the channel current of nAChR could be inhibitted by ketamine.Activating cholinergic receptor or increasing acetylcholine level coud alleviate ketamine induced neuronal apoptosis while blocking cholinergic receptor could induce neuronal apoptosis that similar to ketamine’s effect.These findings indicated that nAChR and transition of spontaneous cholinergic network activity to glutamatergic network activity may contribute to ketamine-induced neuronal apoptosis during the peak period of synaptogenesis.In addition,we investigated the effect and possible mechanism of PACAP38 on ketamine-induced neuronal apoptosis;we found that PACAP38 could alleviate ketamine-induced neuronal apoptosis in ganglion cell layer of P7 rat retina.The protective effect of PACAP38 could be inhibitted by Adenylate cyclase(AC)inhibitor,Protein Kinase A(PKA)inhibitor and Extracellular regulated protein kinases(ERK1/2)inhibitor,which demonstrated that the anti-apoptotic effect of PACAP38 mainly attributes to cAMP/PKA signaling pathway and active ERK1/2.