Sodium channel Na_v1.6 involved in modulating isoflurane-induced perioperative cognitive disorder of mice

Perioperative neurocognitive disorder (PND), a major contributor to poor postoperative outcomes and excessive healthcare costs, has been associated with isoflurane inhalation, although the underlying mechanisms remain poorly defined. Voltage-gated sodium channels (VGSCs or Na_v) have been implicated in mediating the anesthetic effects of isoflurane. We previously reported that the Na_v1.6 subtype modulates neural network activity and cognitive function. Here we investigated whether Na_v1.6-mediated network disturbances contribute to isoflurane-induced PND. In the present study, we observed an increase in hippocampal Na_v1.6 expression, accompanied by abnormal neural network excitability characterized by decreased β- and γ-band power on electroencephalogram (EEG) recordings. This dysfunction led to excessive glutamate release and subsequent cognitive impairment. Correspondingly, downregulation of Na_v1.6 by lidocaine abolished both the abnormal network excitability and excessive glutamate release in isoflurane-exposed mice. In parallel, changes in excitatory synaptic proteins and excitatory amino acid transporters contributed to improved cognitive performance in isoflurane-inhaled mice. Taken together, isoflurane-induced increase in Na_v1.6 evokes the abnormal network excitability, leading to excessive glutamate release and eventually cognitive decline. Our study offers a novel potential mechanism linking Na_v1.6 to isoflurane-induced PND and suggests lidocaine as a potential therapeutic candidate.