Sodium channel Nav1.6 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 Nav) have been implicated in mediating the anesthetic effects of isoflurane. We previously reported that the Nav1.6 subtype modulates neural network activity and cognitive function. Here we investigated whether Nav1.6-mediated network disturbances contribute to isoflurane-induced PND. In the present study, we observed an increase in hippocampal Nav1.6 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 Nav1.6 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 Nav1.6 evokes the abnormal network excitability, leading to excessive glutamate release and eventually cognitive decline. Our study offers a novel potential mechanism linking Nav1.6 to isoflurane-induced PND and suggests lidocaine as a potential therapeutic candidate.