The M-current works in tandem with the persistent sodium current to set the speed of locomotion

Jérémy Verneuil; Cécile Brocard; Virginie Trouplin; Laurent Villard; Julie Peyronnet-Roux; Frédéric Brocard

doi:10.1371/journal.pbio.3000738

The M-current works in tandem with the persistent sodium current to set the speed of locomotion

PLoS Biol. 2020 Nov 13;18(11):e3000738. doi: 10.1371/journal.pbio.3000738. eCollection 2020 Nov.

Authors

Jérémy Verneuil¹, Cécile Brocard¹, Virginie Trouplin¹, Laurent Villard², Julie Peyronnet-Roux¹, Frédéric Brocard¹

Affiliations

¹ Institut de Neurosciences de la Timone, Aix-Marseille Université and Centre National de la Recherche Scientifique, Marseille, France.
² Aix-Marseille Université, Inserm, MMG, Marseille, France.

Abstract

The central pattern generator (CPG) for locomotion is a set of pacemaker neurons endowed with inherent bursting driven by the persistent sodium current (INaP). How they proceed to regulate the locomotor rhythm remained unknown. Here, in neonatal rodents, we identified a persistent potassium current critical in regulating pacemakers and locomotion speed. This current recapitulates features of the M-current (IM): a subthreshold noninactivating outward current blocked by 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) and enhanced by N-(2-chloro-5-pyrimidinyl)-3,4-difluorobenzamide (ICA73). Immunostaining and mutant mice highlight an important role of Kv7.2-containing channels in mediating IM. Pharmacological modulation of IM regulates the emergence and the frequency regime of both pacemaker and CPG activities and controls the speed of locomotion. Computational models captured these results and showed how an interplay between IM and INaP endows the locomotor CPG with rhythmogenic properties. Overall, this study provides fundamental insights into how IM and INaP work in tandem to set the speed of locomotion.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn / metabolism
Animals, Newborn / physiology
Anthracenes / pharmacology
Central Pattern Generators / metabolism*
Central Pattern Generators / physiology
KCNQ2 Potassium Channel / genetics
KCNQ2 Potassium Channel / metabolism*
Locomotion / physiology*
Male
Mice, Inbred C57BL
Motor Neurons / metabolism
Motor Neurons / physiology
Neurons / physiology
Potassium / metabolism
Potassium Channels / metabolism
Rats
Rats, Wistar
Sodium / metabolism
Sodium Channels / metabolism
Sodium Channels / physiology
Spinal Cord / physiology
Walking / physiology

Substances

10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
Anthracenes
KCNQ2 Potassium Channel
Potassium Channels
Sodium Channels
Sodium
Potassium

Grants and funding

This research was financed by grants from French National Research Agency (CalpaSCI, ANR-16-CE16-0004; IMprove, ANR-19-CE17-0018) and the French Institut pour la Recherche sur la Moelle épinière et l’Encéphale (IRME). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.