Kole, MaartenIlschner, Susanne DRKampa, BjoernWilliams, StephenRuben, PeterStuart, Gregory J2015-12-071097-6256http://hdl.handle.net/1885/19967The 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.Keywords: actin; sodium ion; voltage gated sodium channel; action potential; animal cell; animal experiment; article; controlled study; cytoskeleton; dendrite; density; imaging system; immunohistochemistry; nerve fiber; nonhuman; priority journal; pyramidal nerve c200810.1038/nn20402015-12-07