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Synaptic mechanisms underlying modulation of locomotor-related motoneuron output by premotor cholinergic interneurons

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Author(s)

Filipe Nascimento, Matthew James Broadhead, Efstathia Tetringa, Eirini Tsape, Laskaro Zagoraiou, Gareth Brian Miles

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Abstract

Spinal motor networks are formed by diverse populations of interneurons that set the strength and rhythmicity of behaviors such as locomotion. A small cluster of cholinergic interneurons, expressing the transcription factor Pitx2, modulates the intensity of muscle activation via ‘C-bouton’ inputs to motoneurons. However, the synaptic mechanisms underlying this neuromodulation remain unclear. Here, we confirm in mice that Pitx2+ interneurons are active during fictive locomotion and that their chemogenetic inhibition reduces the amplitude of motor output. Furthermore, after genetic ablation of cholinergic Pitx2+ interneurons, M2 receptor-dependent regulation of the intensity of locomotor output is lost. Conversely, chemogenetic stimulation of Pitx2+ interneurons leads to activation of M2 receptors on motoneurons, regulation of Kv2.1 channels and greater motoneuron output due to an increase in the inter-spike afterhyperpolarization and a reduction in spike half-width. Our findings elucidate synaptic mechanisms by which cholinergic spinal interneurons modulate the final common pathway for motor output.
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Original languageEnglish
Article numbere54170
Number of pages26
JournaleLife
Volume9
DOIs
Publication statusPublished - 9 Mar 2020

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