ID: 216598 Effects of Sodium Channel Clustering on Activation Thresholds of Nonmyelinated Axons

Abstract

It is hypothesized that some neurostimulation therapies, such as dorsal root ganglion stimulation (DRGS), may provide therapeutic benefit by activating nonmyelinated neurons (e.g., C-neurons). However, conventional neurostimulation theory suggests that extracellular electrical stimulation preferentially activates large-diameter myelinated neurons over small-diameter nonmyelinated neurons. Interestingly, a recent study of DRGS in rats demonstrated that the activation thresholds of nonmyelinated C-neurons are only ∼1.5 times greater than the activation thresholds of myelinated Abeta-neurons (Chao et al., 2020). It is possible that certain electrophysiological features of C-type neurons unaccounted for in previous computational models could reduce activation thresholds to ranges comparable to the thresholds of myelinated neurons. For example, Nav1.8 sodium channels, which underlie most of the sodium current during the upstroke of action potentials in some C-neurons, have been shown to be distributed in clusters along the axons of C-type neurons forming so-called “micro-nodes” (Pristerà et al., 2012). In this study, we developed a computational model to investigate the impact of Nav1.8-channel clustering on the threshold for action potential generation in nonmyelinated axons.