Trpm5 channels encode bistability of spinal motoneurons and ensure motor control of hindlimbs in mice

Rémi Bos,Frédéric Brocard,Virginie Trouplin,Mouloud Bouhadfane,Benoît Drouillas,Emilie Pecchi,Sergiy M. Korogod

doi:10.1038/s41467-021-27113-x

Abstract

Bistable motoneurons of the spinal cord exhibit warmth-activated plateau potential driven by Na+ and triggered by a brief excitation. The thermoregulating molecular mechanisms of bistability and their role in motor functions remain unknown. Here, we identify thermosensitive Na+-permeable Trpm5 channels as the main molecular players for bistability in mouse motoneurons. Pharmacological, genetic or computational inhibition of Trpm5 occlude bistable-related properties (slow afterdepolarization, windup, plateau potentials) and reduce spinal locomotor outputs while central pattern generators for locomotion operate normally. At cellular level, Trpm5 is activated by a ryanodine-mediated Ca2+ release and turned off by Ca2+ reuptake through the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump. Mice in which Trpm5 is genetically silenced in most lumbar motoneurons develop hindlimb paresis and show difficulties in executing high-demanding locomotor tasks. Overall, by encoding bistability in motoneurons, Trpm5 appears indispensable for producing a postural tone in hindlimbs and amplifying the locomotor output.

Highlights

Bistable motoneurons of the spinal cord exhibit warmth-activated plateau potential driven by Na+ and triggered by a brief excitation
ΔV was of 7.3 ± 0.5 MN (%) V (mV) in mean, whereas it was null in non-bistable motoneurons (Supplementary Fig. 1d)
Dantrolene, caffeine, and thapsigargin modulated slow afterdepolarization (sADP) without affecting either Ca2+ spikes or input resistance of the cell (Supplementary Fig. 6). These results show that Ca2+ entering through the voltage-gated Ca2+ channels act as a trigger giving rise to further Ca2+ release from intracellular stores through ryanodine receptors (RyR) and thereby recruits Trpm[5] channels

Summary

Introduction

Bistable motoneurons of the spinal cord exhibit warmth-activated plateau potential driven by Na+ and triggered by a brief excitation. We used a combination of cellular, electrophysiological, computational, behavioral, and genetic approaches to identify the channel(s) underlying ICaN in motoneurons and determine the functional role(s) of ICaN-dependent plateau potentials in motor behaviors. Our attention turned to a family of cationic channels called transient receptor potential (TRP) channels and in particular to two closely related TRP channels of the melastatin subfamily, Trpm[4] and Trpm[5] Both channels are (i) warmth-activated, (ii) Ca2+-activated, (iii) permeable to Na+ but not to Ca2+, (iv) capable of maintaining a sustained depolarization[34,35,36,37]. We report Trpm[5], but not Trpm[4], as the main Na+-permeant channel mediating the warmth-activated ICaN and provide evidence of its critical role in generating plateau potentials in bistable motoneurons. We assigned to bistable motoneurons a behavioral role in both posture and high-demanding locomotor tasks

Methods

Results

Conclusion