Calcineurin/P-ERK/Egr-1 Pathway Is Involved In Fear Memory Impairment After Isoflurane Exposure In Mice

Background:Isofurane exposure adversely infuences subsequent fear memory formation in mice.Calcineurin(CaN),a phosphatase,prevents the establishment of emotional memory by dephosphorylating substrates and inhibiting the expression of learning and memory related genes.We therefore hypothesize that the impairment of fear memory formation by isoflurane was associated with altered CaN activity and downstream phosphorylated-extracellular signal-regulated kinases(p-ERK)and early growth response gene-1(Egr-1)expression in hippocampus and amygdala.Based on this hypothesis,we tested whether memory performance impairment induced by isoflurane rxposure can be rescued by the CaN inhibitor FK506 and p-ERK activator ceramide C6.Methods:1.Adult C57BL/6 mice were injected FK506/vehicle after being exposed to 1.3%isoflurane or air+O2 for 1 h,or injected ceramide C6/vehicle 30min before isoflurane or air+O2 exposure.After a 1h or 24h or 7d-recovery,mice underwent classical fear conditioning(FC)training.Fear memory to context and tone were tested 24h after training.2.The expression and activity of CaN,phosphorylation of ERK and the expression of Egr-1 in hippocampus and amygdala were analyzed.Results:1.Isoflurane exposure reduced mice freezing time in contextual and tone FC tests 24h after training.Hippocampus and amygdala from isoflurane-exposed mice had enhanced CaN activity,reduced p-ERK/ERK and Egr-1 expression.2.All these changes in isoflurane-exposed mice were attenuated by FK506 and ceramide C6 treatment.Conclusions:These results indicate that calcineurin/p-ERK/Egr-1 Pathway is involved in fear memory impairment after isoflurane exposure in mice.