Calcineurin/P-ERK/Egr-1 Pathway is Involved in Fear Memory Impairment after Isoflurane Exposure in Mice

Isoflurane exposure adversely influences 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 investigated whether isoflurane impairment of fear memory formation 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. We also tested whether memory performance can be rescued by the CaN inhibitor FK506. Adult C57BL/6 mice were injected FK506 or vehicle after being exposed to 1.3% isoflurane or air for 1 h. After a 1 h- recovery, mice underwent classical fear conditioning (FC) training. Fear memory were tested 30 min, 48 h and 7 days after training. The activity of CaN, and expression of p-ERK and Egr-1 in hippocampus and amygdala were analyzed. Isoflurane exposure reduced mice freezing time in contextual and tone FC tests 30 min and 48 h after training. Hippocampus and amygdala from isoflurane-exposed mice had enhanced CaN activity, reduced p-ERK/ERK and Egr-1 expression. All these changes in isoflurane-exposed mice were attenuated by FK506 treatment. These results indicate calcineurin/p-ERK/Egr-1 Pathway is involved in fear memory impairment after isoflurane exposure in mice.