Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors

Abstract Neuromodulation ensures that neural circuits produce output that is flexible whilst remaining within an optimal operational range. The neuromodulator acetylcholine is released during locomotion to regulate spinal motor circuits. However, the range of receptors and downstream mechanisms by w...

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Autores principales:	Filipe Nascimento, Lennart R. B. Spindler, Gareth B. Miles
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ead154b865504c6eb379cbf73316014b
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spelling	oai:doaj.org-article:ead154b865504c6eb379cbf73316014b2021-12-02T15:09:54ZBalanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors10.1038/s41598-019-50452-12045-2322https://doaj.org/article/ead154b865504c6eb379cbf73316014b2019-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-50452-1https://doaj.org/toc/2045-2322Abstract Neuromodulation ensures that neural circuits produce output that is flexible whilst remaining within an optimal operational range. The neuromodulator acetylcholine is released during locomotion to regulate spinal motor circuits. However, the range of receptors and downstream mechanisms by which acetylcholine acts have yet to be fully elucidated. We therefore investigated metabotropic acetylcholine receptor-mediated modulation by using isolated spinal cord preparations from neonatal mice in which locomotor-related output can be induced pharmacologically. We report that M2 receptor blockade decreases the frequency and amplitude of locomotor-related activity, whilst reducing its variability. In contrast, M3 receptor blockade destabilizes locomotor-related bursting. Motoneuron recordings from spinal cord slices revealed that activation of M2 receptors induces an outward current, decreases rheobase, reduces the medium afterhyperpolarization, shortens spike duration and decreases synaptic inputs. In contrast, M3 receptor activation elicits an inward current, increases rheobase, extends action potential duration and increases synaptic inputs. Analysis of miniature postsynaptic currents support that M2 and M3 receptors modulate synaptic transmission via different mechanisms. In summary, we demonstrate that M2 and M3 receptors have opposing modulatory actions on locomotor circuit output, likely reflecting contrasting cellular mechanisms of action. Thus, intraspinal cholinergic systems mediate balanced, multimodal control of spinal motor output.Filipe NascimentoLennart R. B. SpindlerGareth B. MilesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-16 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Filipe Nascimento Lennart R. B. Spindler Gareth B. Miles Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors
description	Abstract Neuromodulation ensures that neural circuits produce output that is flexible whilst remaining within an optimal operational range. The neuromodulator acetylcholine is released during locomotion to regulate spinal motor circuits. However, the range of receptors and downstream mechanisms by which acetylcholine acts have yet to be fully elucidated. We therefore investigated metabotropic acetylcholine receptor-mediated modulation by using isolated spinal cord preparations from neonatal mice in which locomotor-related output can be induced pharmacologically. We report that M2 receptor blockade decreases the frequency and amplitude of locomotor-related activity, whilst reducing its variability. In contrast, M3 receptor blockade destabilizes locomotor-related bursting. Motoneuron recordings from spinal cord slices revealed that activation of M2 receptors induces an outward current, decreases rheobase, reduces the medium afterhyperpolarization, shortens spike duration and decreases synaptic inputs. In contrast, M3 receptor activation elicits an inward current, increases rheobase, extends action potential duration and increases synaptic inputs. Analysis of miniature postsynaptic currents support that M2 and M3 receptors modulate synaptic transmission via different mechanisms. In summary, we demonstrate that M2 and M3 receptors have opposing modulatory actions on locomotor circuit output, likely reflecting contrasting cellular mechanisms of action. Thus, intraspinal cholinergic systems mediate balanced, multimodal control of spinal motor output.
format	article
author	Filipe Nascimento Lennart R. B. Spindler Gareth B. Miles
author_facet	Filipe Nascimento Lennart R. B. Spindler Gareth B. Miles
author_sort	Filipe Nascimento
title	Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors
title_short	Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors
title_full	Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors
title_fullStr	Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors
title_full_unstemmed	Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors
title_sort	balanced cholinergic modulation of spinal locomotor circuits via m2 and m3 muscarinic receptors
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/ead154b865504c6eb379cbf73316014b
work_keys_str_mv	AT filipenascimento balancedcholinergicmodulationofspinallocomotorcircuitsviam2andm3muscarinicreceptors AT lennartrbspindler balancedcholinergicmodulationofspinallocomotorcircuitsviam2andm3muscarinicreceptors AT garethbmiles balancedcholinergicmodulationofspinallocomotorcircuitsviam2andm3muscarinicreceptors
_version_	1718387788117704704

Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors

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