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Differential regulation of NMDA receptors by D-serine and glycine in mammalian spinal locomotor networks

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Date
01/05/2017
Author
Acton, David
Miles, Gareth B.
Keywords
Motor control
Central pattern generator
Spinal cord
Neuromodulation
RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
NDAS
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Abstract
Activation of N-methyl-d-aspartate receptors (NMDARs) requires the binding of a coagonist, either d-serine or glycine, in addition to glutamate. Changes in occupancy of the coagonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR coagonist binding site in mammalian spinal locomotor networks. Blockade of NMDARs by d(−)-2-amino-5-phosphonopentanoic acid (d-APV) or 5,7-dichlorokynurenic acid reduced the frequency and amplitude of pharmacologically induced locomotor-related activity recorded from the ventral roots of spinal-cord preparations from neonatal mice. Furthermore, d-APV abolished synchronous activity induced by blockade of inhibitory transmission. These results demonstrate an important role for NMDARs in murine locomotor networks. Bath-applied d-serine enhanced the frequency of locomotor-related but not disinhibited bursting, indicating that coagonist binding sites are saturated during the latter but not the former mode of activity. Depletion of endogenous d-serine by d-amino acid oxidase or the serine-racemase inhibitor erythro-β-hydroxy-l-aspartic acid (HOAsp) increased the frequency of locomotor-related activity, whereas application of l-serine to enhance endogenous d-serine synthesis reduced burst frequency, suggesting a requirement for d-serine at a subset of synapses onto inhibitory interneurons. Consistent with this, HOAsp was ineffective during disinhibited activity. Bath-applied glycine (1–100 µM) failed to alter locomotor-related activity, whereas ALX 5407, a selective inhibitor of glycine transporter-1 (GlyT1), enhanced burst frequency, supporting a role for GlyT1 in NMDAR regulation. Together these findings indicate activity-dependent and synapse-specific regulation of the coagonist binding site within spinal locomotor networks, illustrating the importance of NMDAR regulation in shaping motor output.
Citation
Acton , D & Miles , G B 2017 , ' Differential regulation of NMDA receptors by D-serine and glycine in mammalian spinal locomotor networks ' , Journal of Neurophysiology , vol. 117 , no. 5 , pp. 1877-1893 . https://doi.org/10.1152/jn.00810.2016
Publication
Journal of Neurophysiology
Status
Peer reviewed
DOI
https://doi.org/10.1152/jn.00810.2016
ISSN
0022-3077
Type
Journal article
Rights
Copyright © 2017 the American Physiological Society Licensed under Creative Commons Attribution CC-BY 3.0: © the American Physiological Society.
Description
This work was supported by an Institutional Strategic Support Fund grant from the Wellcome Trust.
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  • University of St Andrews Research
URL
http://jn.physiology.org/content/117/5/1877.figures-only
URI
http://hdl.handle.net/10023/10809

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