Spontaneous and tonic action potential firing is sustained by membrane potential instabilities in peripheral sensory neurons

Sustained action potential firing (SAPF) is a feature shared by multiple neuronal types and is crucial for stimulus encoding, neural communication and circuit plasticity. We aimed at unveiling the mechanisms underlying SAPF in Peripheral Sensory Neurons (PSNs), a convenient experimental model for studying single-cell excitability. Current-clamp recordings in primary-cultured PSNs revealed that tonic depolarization elicits Subthreshold Membrane Potential Transients (SMPTs) in 82% of this cells, and statistical analyses indicates that larger and faster SMPTs are causally associated with SAPF. Pharmacological or genetic ablation of the voltage-gated Na+ channel NaV1.9 reduced both SMPTs and SAPF. Computational models of neuronal electrical activity revealed that stochasticity of NaV and KV channels gating is necessary and sufficient for the generation of SMPTs and SAPF. Behavioral tests showed that NaV1.9 KO mice are severely impaired in detecting slow and tonic noxious thermal stimuli. We conclude that stochastic openings of NaV1.9 channels result in SMPTs that support SAPF and, consequently, nocifensive responses to slow and tonic noxious stimuli that are critical for animal adaptation and survival.