Effects of transient, persistent, and resurgent sodium currents on excitability and spike regularity in vestibular ganglion neurons.

Abstract

Vestibular afferent neurons occur as two populations with differences in spike timing regularity that are independent of rate. The more excitable regular afferents have lower current thresholds and sustained spiking responses to injected currents, while irregular afferent neurons have higher thresholds and transient responses. Differences in expression of low-voltage-activated potassium (K _LV ) channels are emphasized in models of spiking regularity and excitability in these neurons, leaving open the potential contributions of the voltage-gated sodium (Na _V ) channels responsible for the spike upstroke. We investigated the impact of different Na _V current modes (transient, persistent, and resurgent) with whole-cell patch clamp experiments in mouse vestibular ganglion neurons (VGNs), the cultured and dissociated cell bodies of afferents. All VGNs had transient Na _V current, many had a small persistent (non-inactivating) Na _V current, and a few had resurgent current, which flows after the spike peak when Na _V channels that were blocked are unblocked. Na _V 1.6 channels conducted most or all of each Na _V current mode, and a Na _V 1.6-selective blocker decreased spike rate and altered spike waveforms in both sustained and transient VGNs. A Na _V channel agonist enhanced persistent current and increased spike rate and regularity. We hypothesized that persistent and resurgent currents have different effects on sustained (regular) VGNs vs. transient (irregular) VGNs. Lacking blockers specific for the different current modes, we used modeling to isolate their effects on spiking of simulated transient and sustained VGNs, driven by simulated current steps and noisy trains of simulated EPSCs. In all simulated neurons, increasing transient Na _V current increased spike rate and rate-independent regularity. In simulated sustained VGNs, adding persistent current increased both rate and rate-independent regularity, while adding resurgent current had limited impact. In transient VGNs, adding persistent current had little impact, while adding resurgent current increased both rate and rate-independent irregularity by enhancing sensitivity to synaptic noise. These experiments show that the small Na _V current modes may enhance the differentiation of afferent populations, with persistent currents selectively making regular afferents more regular and resurgent currents selectively making irregular afferents less regular.