Abstract

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 Na_v1.6 and high-threshold Na_v1.2 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 Na_v1.6 promotes action potential initiation, whereas proximal Na_v1.2 promotes its backpropagation to the soma.

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