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

  • Br J Anaesth. 2017 Nov 1;119(5):1047-1054. doi: 10.1093/bja/aex043.
P Liang  1  2 ,  F Li  1 ,  J Liu  1  2 ,  D Liao  1 ,  H Huang  1  3 ,  C Zhou  1
Affiliations
  • 1. Laboratory of Anaesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, China.
  • 2. Department of Anaesthesiology, West China Hospital of Sichuan University, China.
  • 3. Department of Anaesthesiology, West China Second Hospital of Sichuan University, Sichuan, China.
PMID: 28981700 DOI: 10.1093/bja/aex043
Abstract

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.

Keywords
GluK2; animal model; brain slice; electrophysiology; hyperactivity; kainate receptors; mice behaviour; seizure; sevoflurane; volatile anaesthetics.
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