Influence of NaV Subtypes in the AIS on Backpropagation in a Simulated Pyramidal Neuron

Abstract

1AbstractIn a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS). Pyramidal neurons concentrate high-threshold sodium channels (NaV1.2) in the proximal AIS, and the distal AIS contains mostly lower threshold NaV1.6. It has been argued that this separated NaV distribution favors the backpropagation of APs from the AIS to the dendrites. However, our simulations show that this distribution actually impedes backpropagation when the neuron is stimulated somatically. We implemented a range of hypothetical NaV distributions in the AIS of a multicompartmental pyramidal cell model. When a stimulating current is injected at the soma, the intrinsic right-shift of NaV1.2 activation causes these channels to raise the backpropagation threshold. However, with axonal stimulation, the right-shift of NaV1.2 availability dominates, such that concentrating NaV1.2 in the proximal AIS promotes backpropagation. Our results imply that regulation of NaV separation can sensitively control backpropagation and that prior experiments can be reconciled by comparing the two modes of stimulation.