- In cortical pyramidal neurons, the axon initial segment (AIS) is pivotal in synaptic integration. It has been asserted that this is because there is a high density of Na(+) channels in the AIS. However, we found that action potential-associated Na(+) flux, as measured by high-speed fluorescence Na(+) imaging, was about threefold larger in the rat AIS than in the soma. Spike-evoked Na(+) flux in the AIS and the first node of Ranvier was similar and was eightfold lower in basal dendrites. At near-threshold voltages, persistent Na(+) conductance was almost entirely axonal. On a time scale of seconds, passive diffusion, and not pumping, was responsible for maintaining transmembrane Na(+) gradients in thin axons during high-frequency action potential firing. In computer simulations, these data were consistent with the known features of action potential generation in these neurons.