Resurgent Na+ Current Offers Noise Modulation in Bursting Neurons

Neurons utilize bursts of action potentials as an efficient and reliable way to encode information. It is likely that the intrinsic membrane properties of neurons involved in burst generation may also participate in preserving its temporal features. Here we examined the contribution of the persistent and resurgent components of voltage-gated Na+ currents in modulating the burst discharge in sensory neurons. Using mathematical modeling, theory and dynamic-clamp electrophysiology, we show that, distinct from the persistent Na+ component which is important for membrane resonance and burst generation, the resurgent Na+ can help stabilize burst timing features including the duration and intervals. Moreover, such a physiological role for the resurgent Na+ offered noise tolerance and preserved the regularity of burst patterns. Model analysis further predicted a negative feedback loop between the persistent and resurgent gating variables which mediate such gain in burst stability. These results highlight a novel role for the voltage-gated resurgent Na+ component in moderating the entropy of burst-encoded neural information.Author summary: The nervous system extracts meaningful information from natural environments to guide precise behaviors. Sensory neurons encode and relay such complex peripheral information as electrical events, known as action potentials or spikes. The timing intervals between the spikes carry stimulus-relevant information. Therefore, disruption of spike timing by random perturbations can compromise the nervous system function. In this study we investigated whether the widely-distributed voltage-gated sodium (Na+) ion channels important for spike generation can also serve as noise modulators in sensory neurons. We developed and utilized mathematical models for the different experimentally inseparable components of a complex Na+ channel current. This enabled phenomenological simplification and examination of the individual roles of Na+ components in spike timing control. We further utilized real-time closed-loop experiments to validate model predictions, and theoretical analysis to explain experimental outcomes. Using such multifaceted approach, we uncovered a novel role for a resurgent Na+ component in enhancing the reliability of spike timing and in noise modulation. Furthermore, our simplified model can be utilized in future computational and experimental studies to better understand the pathological consequences of Na+ channelopathies.