A potential mechanism and strategy for accelerating recovery of neurocognitive function after general anaesthesia through store‐operated Orai1 channels

BACKGROUND AND PURPOSE: homeostasis, potentially involving store-operated Orai1 channels, is one proposed mechanism. The study investigated the role of Orai1 channels in inhibitory neurons. EXPERIMENTAL APPROACH: Behavioural data before and 1 h after general anaesthesia (1 minimum alveolar concentration (MAC) for 30 min) were compared in wild-type (WT) and knockout (KO) mice, in which Orai1 was specifically deleted in inhibitory interneurons. To examine the underlying mechanisms, electrophysiological studies were performed using brain slices and hippocampal neuroinflammation was assessed by enzyme-linked immunosorbent assay. KEY RESULTS: The success rate of the Y-maze test significantly decreased after sevoflurane anaesthesia in WT but not in KO mice, with similar results after isoflurane and longer duration sevoflurane (1 h) anaesthesia. Hippocampal long-term potentiation showed a similar reduction after sevoflurane in WT but not in KO mice. Whole-cell patch-clamp recordings from CA1 interneurons revealed that the sevoflurane-induced increase in the frequency of spontaneous inhibitory postsynaptic currents in WT was diminished by tetrodotoxin, whereas no significant increase was observed in KO mice. Hippocampal TNFα levels were significantly higher after sevoflurane in WT but not in KO mice. Pre-administration of an Orai1 channel inhibitor showed a similar decrease in the Y-maze test after sevoflurane anaesthesia. CONCLUSION AND IMPLICATIONS: Store-operated Orai1 channels in inhibitory neurons could play a critical role in delayed recovery following general anaesthesia, potentially by regulating action potential generation. Pharmacological inhibition of the channels may prevent perioperative neurocognitive disorder.