The volatile anesthetic isoflurane differentially inhibits voltage-gated sodium channel currents between pyramidal and parvalbumin neurons in the prefrontal cortex

BackgroundHow volatile anesthetics work remains poorly understood. Modulations of synaptic neurotransmission are the direct cellular mechanisms of volatile anesthetics in the central nervous system. Volatile anesthetics such as isoflurane may reduce neuronal interaction by differentially inhibiting neurotransmission between GABAergic and glutamatergic synapses. Presynaptic voltage-dependent sodium channels (Na-v), which are strictly coupled with synaptic vesicle exocytosis, are inhibited by volatile anesthetics and may contribute to the selectivity of isoflurane between GABAergic and glutamatergic synapses. However, it is still unknown how isoflurane at clinical concentrations differentially modulates Na-v currents between excitatory and inhibitory neurons at the tissue level. MethodsIn this study, an electrophysiological recording was applied in cortex slices to investigate the effects of isoflurane on Na-v between parvalbumin (PV+) and pyramidal neurons in PV-cre-tdTomato and/or vglut2-cre-tdTomato mice. ResultsIsoflurane at clinically relevant concentrations produced a hyperpolarizing shift in the voltage-dependent inactivation and slowed the recovery time from the fast inactivation in both cellular subtypes. Since the voltage of half-maximal inactivation was significantly depolarized in PV+ neurons compared to that of pyramidal neurons, isoflurane inhibited the peak Na-v currents in pyramidal neurons more potently than those of PV+ neurons (35.95 & PLUSMN; 13.32% vs. 19.24 & PLUSMN; 16.04%, P = 0.036 by the Mann-Whitney test). ConclusionsIsoflurane differentially inhibits Na-v currents between pyramidal and PV+ neurons in the prefrontal cortex, which may contribute to the preferential suppression of glutamate release over GABA release, resulting in the net depression of excitatory-inhibitory circuits in the prefrontal cortex.

Automated summary

The mechanisms of volatile anesthetics in the central nervous system are mainly through the modulation of synaptic neurotransmission. Isoflurane can selectively inhibit neurotransmission in GABAergic and glutamatergic synapses, which is related to the modulation of presynaptic voltage-dependent sodium channels. This study examined the effects of isoflurane on sodium currents in different types of neurons in the prefrontal cortex and found that isoflurane inhibited sodium currents more potently in pyramidal neurons than in PV+ neurons.