Role of sodium channel subtype in action potential generation by neocortical pyramidal neurons

Neocortical pyramidal neurons express several distinct subtypes of voltage-gated Na⁺ channels. In mature cells, Na_v1.6 is the dominant channel subtype in the axon initial segment (AIS) as well as in the nodes of Ranvier. Action potentials (APs) are initiated in the AIS, and it has been proposed that the high excitability of this region is related to the unique characteristics of the Na_v1.6 channel. Knockout or loss-of-function mutation of the Scn8a gene is generally lethal early in life because of the importance of this subtype in noncortical regions of the nervous system. Using the Cre/loxP system, we selectively deleted Na_v1.6 in excitatory neurons of the forebrain and characterized the excitability of Na_v1.6-deficient layer 5 pyramidal neurons by patch-clamp and Na⁺ and Ca²⁺ imaging recordings. We now report that, in the absence of Na_v1.6 expression, the AIS is occupied by Na_v1.2 channels. However, APs are generated in the AIS, and differences in AP propagation to soma and dendrites are minimal. Moreover, the channels that are expressed in the AIS still show a clear hyperpolarizing shift in voltage dependence of activation, compared with somatic channels. The only major difference between Na_v1.6-null and wild-type neurons was a strong reduction in persistent sodium current. We propose that the molecular environment of the AIS confers properties on whatever Na channel subtype is present and that some other benefit must be conferred by the selective axonal presence of the Na_v1.6 channel.