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The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na+ channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na+ channel density. We found that low-threshold Nav1.6 and high-threshold Nav1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na+ current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Nav1.6 promotes action potential initiation, whereas proximal Nav1.2 promotes its backpropagation to the soma. [ABSTRACT FROM AUTHOR]