Action potential generation requires a high sodium channel density in the axon initial segment

The axon initial segment (AIS) is a specialized region in neurons where action potentials are initiated. It is commonly assumed that this process requires a high density of voltage-gated sodium (Na⁺) channels. Paradoxically, the results of patch-clamp studies suggest that the Na ⁺ channel density at the AIS is similar to that at the soma and proximal dendrites. Here we provide data obtained by antibody staining, whole-cell voltage-clamp and Na⁺ imaging, together with modeling, which indicate that the Na⁺ channel density at the AIS of cortical pyramidal neurons is ∼50 times that in the proximal dendrites. Anchoring of Na⁺ channels to the cytoskeleton can explain this discrepancy, as disruption of the actin cytoskeleton increased the Na⁺ current measured in patches from the AIS. Computational models required a high Na ⁺ channel density (∼2,500 pS μm^-2) at the AIS to account for observations on action potential generation and backpropagation. In conclusion, action potential generation requires a high Na⁺ channel density at the AIS, which is maintained by tight anchoring to the actin cytoskeleton.