Sevoflurane activates hippocampal CA3 kainate receptors (Gluk2) to induce hyperactivity during induction and recovery in a mouse model

Background: In addition to general anaesthetic effects, sevoflurane can also induce hyperactive behaviours during induction and recovery, which may contribute to neurotoxicity; however, the mechanism of such effects is unclear. Volatile anaesthetics including isoflurane have been found to activate the kainate (GluK2) receptor. We developed a novel mouse model and further explored the involvement of kainate (GluK2) receptors in sevoflurane-induced hyperactivity.

Methods: Maximal speed, mean speed, total movement distance and resting percentage of C57BL/6 mice were quantitatively measured using behavioural tracking software before and after sevoflurane anaesthesia. Age dependence of this model was also analysed and sevoflurane-induced hyperactivity was evaluated after intracerebral injection of the GluK2 receptor blocker NS-102. Neurones from the hippocampal CA3 region were used to undertake in vitro electrophysiological measurement of kainate currents and miniature excitatory postsynaptic potential (mEPSP).

Results: Sevoflurane induced significant hyperactivities in mice under sevoflurane 1% anaesthesia and during the recovery period, characterized as increased movement speed and total distance. The hyperactivity was significantly increased in young mice compared with adults (P<0.01) and pre-injection of NS-102 significantly prevented this sevoflurane-induced hyperactivity. In electrophysiological experiments, sevoflurane significantly increased the frequency of mEPSP at low concentrations and evoked kainate currents at high concentrations.

Conclusions: We developed a behavioural model in mice that enabled characterization of sevoflurane-induced hyperactivity. The kainate (GluK2) receptor antagonist attenuated these sevoflurane-induced hyperactivities in vivo, suggesting that kainate receptors might be the underlying therapeutic targets for sevoflurane-induced hyperactivities in general anaesthesia.