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

Significance Under most conditions cortical pyramidal neurons are strongly biased to initiate action potentials in the distal part of the axon initial segment (AIS) rather than in the dendrites, where the excitatory postsynaptic potential amplitude is largest. This feature is widely attributed to the axonal presence of the low-threshold Na+ channel subtype Nav1.6. Here, using electrical and high-speed Na+ imaging recordings from Nav1.6 null pyramidal neurons, we demonstrate that the presence of this subunit is neither critical for positioning the spike initiation site within the AIS nor for the spike backpropagation to the dendrites. We also find that one of the most important features of axonal Na+ channel kinetics, the lower activation threshold, is not entirely dependent on the Na+ channel subtype. Neocortical pyramidal neurons express several distinct subtypes of voltage-gated Na+ channels. In mature cells, Nav1.6 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 Nav1.6 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 Nav1.6 in excitatory neurons of the forebrain and characterized the excitability of Nav1.6-deficient layer 5 pyramidal neurons by patch-clamp and Na+ and Ca2+ imaging recordings. We now report that, in the absence of Nav1.6 expression, the AIS is occupied by Nav1.2 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 Nav1.6-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 Nav1.6 channel.