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

In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS), which has a high density of voltage-gated sodium channels (Na V s) on its membrane. In pyramidal neurons, the proximal AIS has been reported to exhibit a higher proportion of Na V s with gating properties that are “ right-shift ed” to more depolarized voltages, compared to the distal AIS. Further, recent experiments have revealed that as neurons develop, the spatial distribution of Na V subtypes along the AIS can change substantially, suggesting that neurons tune their excitability by modifying said distribution. When neurons are stimulated axonally, computational modelling has shown that this spatial separation of gating properties in the AIS enhances the backpropagation of APs into the dendrites. In contrast, in the more natural scenario of somatic stimulation, our simulations show that the same distribution can impede backpropagation. We implemented a range of hypothetical Na V distributions in the AIS of three multicompartmental pyramidal cell models and investigated the precise kinetic mechanisms underlying such effects, as the spatial distribution of Na V subtypes is varied. With axonal stimulation, proximal Na V availability dominates, such that concentrating right-shift ed Na V s in the proximal AIS promotes backpropagation. However, with somatic stimulation, the models are insensitive to availability . Instead, the higher activation threshold of right-shift ed Na V s in the AIS impedes backpropagation. Therefore, recently observed developmental changes to the spatial separation and relative proportions of Na V 1.2 and Na V 1.6 in the AIS differentially impact activation and availability . The effects on backpropagation, and potentially learning, are opposite for orthodromic versus antidromic stimulation. Author Summary Neurons use sodium ion currents, controlled by a neuron’s voltage, to trigger signals called action potentials (APs). These APs typically result from synaptic input from other neurons onto the dendrites and soma. An AP is generated at the axon initial segment (AIS) just beyond the soma. From there, it travels down the axon to other cells, but can also propagate “backwards” towards the soma and dendrites. This “backpropagation” allows a comparison at synapses of the timing of outgoing and incoming signals, a feedback process that modifies synaptic connection strengths linked to learning. It is puzzling that in many neurons, sodium ion channels come in two types: high-voltage threshold channels clustered near the soma where the AIS begins, and low-voltage ones further away towards the axon. This separation changes in the early development of the animal, which raises the question of its role in backpropagation. We constructed a detailed mathematical model to explore how separation affects backpropagation. Separation either impedes or enhances learning, depending on whether the AP results from synaptic inputs or, less typically, currents moving backwards from the axon. This is explained by the different effects the separation has on two key kinetic processes that govern sodium currents.