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Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signalling

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Date
01/09/2018
Author
Acton, David
Broadhead, Matthew J.
Miles, Gareth B.
Funder
The Wellcome Trust
BBSRC
Grant ID
BB/M021793/1
Keywords
Neuromodulation
Metamodulation
Gliotransmission
Central pattern generator
CPG
Motor control
PAR1
BF Psychology
QP Physiology
RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
NDAS
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Abstract
Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14–22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output.
Citation
Acton , D , Broadhead , M J & Miles , G B 2018 , ' Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D 1 -like dopamine receptor signalling ' , Journal of Neurophysiology , vol. 120 , no. 3 , pp. 998-1009 . https://doi.org/10.1152/jn.00783.2017
Publication
Journal of Neurophysiology
Status
Peer reviewed
DOI
https://doi.org/10.1152/jn.00783.2017
ISSN
0022-3077
Type
Journal article
Rights
Copyright © 2018 the American Physiological Society. Licensed under Creative Commons Attribution CC-BY 4.0
Description
D.A. was supported by funds from a Wellcome Trust Institutional Strategic Support Fund grant. G.B.M. and M.J.B. received support from Biotechnology and Biological Science Research Grant BB/M021793/1.
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  • University of St Andrews Research
URL
https://europepmc.org/abstract/MED/29790837
URI
http://hdl.handle.net/10023/15929

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