Interactions among diameter, myelination, and the Na/K pump affect axonal resilience to high-frequency spiking

Axons reliably conduct action potentials between neurons and/or other targets. Axons have widely variable diameters and can be myelinated or unmyelinated. Although the effect of these factors on propagation speed is well studied, how they constrain axonal resilience to high-frequency spiking is incompletely understood. Maximal firing frequencies range from ∼1 Hz to >300 Hz across neurons, but the process by which Na/K pumps counteract Na⁺ influx is slow, and the extent to which slow Na⁺ removal is compatible with high-frequency spiking is unclear. Modeling the process of Na⁺ removal shows that large-diameter axons are more resilient to high-frequency spikes than are small-diameter axons, because of their slow Na⁺ accumulation. In myelinated axons, the myelinated compartments between nodes of Ranvier act as a "reservoir" to slow Na⁺ accumulation and increase the reliability of axonal propagation. We now find that slowing the activation of K⁺ current can increase the Na⁺ influx rate, and the effect of minimizing the overlap between Na⁺ and K⁺ currents on spike propagation resilience depends on complex interactions among diameter, myelination, and the Na/K pump density. Our results suggest that, in neurons with different channel gating kinetic parameters, different strategies may be required to improve the reliability of axonal propagation.