| BackgroundSince 1999,a large number of preclinical studies have shown that commonly used general anesthetics such as sevoflurane and propofol are neurotoxic to the developing brain.According to the data of Anesthesia Quality Institute,around 10%of infants exposed to general anesthetics annually.There are even more infants treated with general anesthetics in China due to the large population of Chinese.The early years life,known as'vulnerable period',are a critical period for children's brain development,as it's a crucial time for synaptogenesis,which makes them more susceptible to external adverse factors.During the synaptogenesis,the postsynaptic membrane adhesion molecules neuroligins(NLGs)are linked to the presynaptic membrane adhesion molecule p-neurexin(P-NRX).These adhesion molecules play an essential role in formation,assembly and differentiation of synapse.Interestingly,their expression peaks at the same period with the peak of synaptogenesis.There are at least four spliced NLGs in mammals,among them,NLG-1 and NLG-2 translocated at excitatory and inhibitory synapses,respectively,then recruits and regulates N-methyl-D-aspartate(NMDA)receptors and y-aminobutyric acid(GABA)A receptors,respectively.Therefore,NLG-1 and NLG-2 play key roles in synaptic differentiation and balance,and the abnormal expression of them are closely associated with a variety of neuropsychiatric disorders.Sevoflurane is a commonly used general anesthetic,which can activate GABAa receptors.Therefore,we speculate that sevoflurane interferes with GABAA receptors of infants;resulting in disordered expression of NLGs,which lead to the imbalance of synaptic differentiation and abnormality of neurobehavior.In the current study,we intended to investigate the effects of sevoflurane on developing brain and the underlying mechanisms.ObjectivesBased on the role of ?-NRX/NLGs in synaptic differentiation and synaptogenesis,as well as their abnormal expression related to the pathogenesis of mental disorders,we hypothesized that neonatal exposed to sevoflurane,acting on GABAa receptor,would disturb the synaptic differentiation and synaptogenesis through ?-NRX/NLGs transsynaptic signals,and consequently lead to long-term emotional disorders and cognitive impairments.Methods and ResultsIn this study,an anesthesia model of sevoflurane pups was randomly divided into control group(Ctrl)and sevoflurane group(Sev).Western blot was used to detect the expression of NRX-1,NLG-1,NLG-2,PSD-95,Gephyrin,alGABAA,NR2A and NR2B in the hippocampus.The expression of NLG-2,Gephyrin and ?1 GABAA in Sev group was significantly increased compared with Ctrl group(NLG-2,P<0.001;Gephyrin,P<0.001;alGABAA>P<0.01);The expression of NLG-1,NRX-1,PSD-95,NR2A and NR2B was significantly decreased in Sev group(NLG-1,P<0.001;NRX-1,P<0.01;PSD-95,P<0.05;NR2A,P<0.001;NR2B,P<0.001).Transmission electron microscopy was used to detect the ratio of excitatory synapses to inhibitory synapses.The proportion of asymmetric synapses in Sev group decreased(P<0.05),while the proportion of symmetric synapses increased(P<0.05).In Golgi staining,the number of dendritic branch and the total dendritic length of hippocampal pyramidal neurons is decreased(P<0.05).The behavioral test showed the latency of the Sev group increased significantly(open field test,P<0.001;water maze test,P<0.01),while there was no significant difference in velocity in the water maze test.ConclusionsThe abnormal expression of ?-NRX/NLGs,excitatory and inhibitory synaptic imbalance and abnormal behavior were caused by sevoflurane exposure in neonatal rats.Therefore,sevoflurane regulate the synaptic development induced by P-NRX/NLGs through GABAA receptor may be one of the important mechanisms of neurotoxicity of general anesthetics. |
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