Impact on backpropagation of the spatial heterogeneity of sodium channel kinetics in the axon initial segment

Abstract

In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS) having favorable cable properties and a high density of voltage-gated ion channels. Pyramidal cells concentrate high-threshold sodium ion channels (NaV1.2) in the proximal AIS, and the distal AIS contains mostly lower threshold NaV1.6. It is widely believed that this separated NaV distribution favors backpropagation and lowers the AP threshold. We implemented a range of hypothetical NaV distributions in the AIS of a multicompartmental pyramidal cell model. Our simulations predict new effects on pyramidal neurons' excitability and backpropagation threshold, caused directly by the naturally occurring spatial separation of NaV1.2 and NaV1.6 in the AIS. By controlling the distribution of NaVs, pyramidal cells create a lengthwise profile of gating properties in the AIS. Using a "shift-clamping" technique, we demonstrate that different gating properties drive the effect of proximal NaV1.2 on the backpropagation threshold when the neuron is stimulated somatically versus axonally. When 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 availability dominates, such that concentrating NaV1.2 in the proximal AIS facilitates backpropagation. The latter effect is dynamic: right-shifting steady-state availability is necessary but not sufficient to facilitate backpropagation; we show that the voltage-sensitive time constant of NaV1.2 availability must be right-shifted as well. Our results imply that regulation of NaV separation can sensitively control backpropagation, especially for somatodendritic stimulation.