Action potential firing and sensory transduction are sustained by membrane potential instabilities in peripheral sensory neurons.

Abstract

Peripheral sensory neurons are fundamental for stimulus detection, but many of their properties remain poorly understood (Velasco et al., 2022). One of these is the marked instability of the resting membrane potential recorded in such neurons, known as Membrane Potential Instabilities (MPIs). MPIs are enhanced in pain states, but their functional significance and molecular bases remain largely unknown. Here, we addressed this using whole-cell current-clamp recordings in primary cultured mouse trigeminal (TG) neurons. MPI detection and morphological analyses were performed semi-automatically, using custom-made scripts. We found that 82.2% of small diameter neurons recorded displayed MPI activity in the shape of Membrane Potential Transients (MPTs), spontaneously or upon depolarizing current injection. The frequency, amplitude and rates of upstroke and repolarization of MPTs were increased by membrane depolarization. Morphological analyses of the MPTs and of the initial depolarizing phase of action potentials (Aps) revealed that larger and faster MPTs precede AP firing. This was confirmed by a regression analysis showing that the maximal rate of depolarization and amplitude of the MPTs strongly predict subsequent AP firing, following a Boltzmann dependency. MPT activity was enhanced by the application of heat, cold, capsaicin and menthol, via their depolarizing effect on the resting membrane potential. MPT activity was reduced by blocking TTX-resistant, but not TTX-sensitive voltage-gated Na+ channels. Accordingly, MPTs were also reduced in neurons isolated from NaV1.8 and NaV1.9 knockout mice. We hereby identify, for the first time, the molecular determinants of the trigger of MPTs and demonstrate a causal relationship between MPTs and AP firing upon exogenous stimulation of sensory neurons. These findings unveil MPTs as crucial regulators of peripheral sensory processing, with possible implications in pathological conditions featuring altered activities of TTX-resistant NaV channels.