Differential roles of Na_V1.2 and Na_V1.6 in neocortical pyramidal cell excitability

Mature neocortical pyramidal cells functionally express two sodium channel (Na_V) isoforms: Na_V1.2 and Na_V1.6. 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_V1.2 and Na_V1.6, along with knock-in mice with changes in Na_V1.2 or Na_V1.6 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_V1.2 and Na_V1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting-and in some situations, opposing-effects on neuronal action potential output, with Na_V1.6 block decreasing and Na_V1.2 block increasing output. Thus, Na_V isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide the development of therapeutics designed to temper hyperexcitability through selective Na_V isoform blockade.