Impact of Sodium Channel Distribution in the Axon Initial Segment on the Initiation and Backpropagation of Action Potentials

We are interested in the biophysics of forward and backward propagation of action potentials (APs), as they are both important for learning. The axon initial segment (AIS) initiates APs in a variety of neurons. Pyramidal cells contain two types of voltage-gated sodium channel: Na_v1.2 (high threshold) and Na_v1.6 (low threshold). These channels are not uniformly distributed in the AIS. The density of Na_v1.2 is greatest near the soma, and Na_v1.6 density peaks further down the AIS, away from the soma. While this distribution is observed, its purpose remains unclear. Counterintuitively, published simulations suggest that concentration of high threshold channels near the soma lowers the threshold for backpropagation. We find that this is true when stimulating at the axon. However, the opposite is true when stimulating at the soma. We propose an intuitive explanation: the cell becomes more excitable —including backpropagation— when the Na_v distribution places more low-threshold channels closer to the site of stimulation. Our results suggest that the observed distribution increases the backpropagation threshold. We use the time-evolution of integrated Na_v current to support this description, and discuss the effect of parameters such as AIS geometry.