MicroRNA-34a negatively regulates anesthesia-induced hippocampal apoptosis and memory impairment through FGFR1.

BACKGROUND

Mounting evidence has shown the toxic effects of anesthesia to neonatal hippocampus. We used an in vivo mouse model to explore the role of microRNA 34a (miR-34a) in regulating anesthesia-induced hippocampal neurotoxicity.

METHODS

One-month old C57/BL6 mice received daily intraperitoneal injection of anesthesia (ketamine, 50 mg/kg) for 7 days. One day after, apoptosis was evaluated by TUNEL staining in hippocampal CA1 region, and expression level of miR-34a assessed by real-time quantitative PCR (qPCR). Hippocampal miR-34a was then down-regulated through lentivirus mediated cortical injection prior to anesthesia. The effects of inhibiting hippocampal miR-34a on anesthesia-induced hippocampal apoptosis and memory impairment were further investigated by TUNEL staining and Morris water maze (MWM) test. The predicted molecular target of miR-34a, fibroblast growth factor receptor 1 (FGFR1) was down-regulated in hippocampus through siRNA-mediated cortical injection and its effect on hippocampal apoptosis was also examined.

RESULTS

Anesthesia caused severe apoptosis among hippocampal CA1 neurons and upregulated hippocampal miR-34a. On the other hand, lentivirual inhibition of miR-34a protected anesthesia-induced hippocampal apoptosis and memory impairment. Luciferase essay demonstrated FGFR1 was directly regulated by miR-34a in hippocampus. siRNA-induced FGFR1 downregulation further exaggerated anesthesia-induced apoptosis in hippocampus.

CONCLUSIONS

Overall, we showed that miR-34a negatively modulated anesthesia-induced hippocampal neurotoxicity.