Differential roles of Na _V 1.2 and Na _V 1.6 in neocortical pyramidal cell excitability

Mature neocortical pyramidal cells functionally express two sodium channel (Na _V ) isoforms: Na _V 1.2 and Na _V 1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of Na _V channels that exhibit state-dependent block of both Na _V 1.2 and Na _V 1.6, along with knock-in mice with changes in Na _V 1.2 or Na _V 1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of Na _V 1.2 and Na _V 1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting-and in some situations, opposing-effects on neuronal action potential output, with Na _V 1.6 block decreasing and Na _V 1.2 block increasing output. Thus, Na _V isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide development of therapeutics designed to temper hyperexcitability through selective Na _V isoform blockade.