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.
Highlights
Locomotion requires a recurrent activation of muscles with variable rhythm to adapt speed of movements as circumstances demand
Rats walked faster when the broad-spectrum activation of Kv7.2–Kv7.5 channels occurred by injecting retigabine (5 mg/kg; see [34]), which was related to a shorter stance phase (P < 0.05, in green, Fig 1A–1C)
IM appears mainly mediated by Kv7.2-containing channels and acts in opposition to INaP by modulating both the emergence and frequency regime of pacemaker cells and thereby regulates the locomotor rhythm
Summary
Locomotion requires a recurrent activation of muscles with variable rhythm to adapt speed of movements as circumstances demand. The rhythm-generating network is a set of pacemaker cells endowed with intrinsic bursting activity in a frequency range similar to stepping rhythms [3, 4]. The immediate assumption was that the locomotor rhythm may emerge from neurons incorporating INaP as a “pacemaker” current. In line with this concept, inhibition of INaP abolishes locomotor-like activity in rodents [3, 9,10,11] and salamanders [12] and disrupts locomotion in zebrafish [8, 13] and Xenopus laevis tadpoles [14]. A picture emerges that the locomotor rhythm arises from a dynamic interplay
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