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Vesicular glutamate release from central axons contributes to myelin damage
The axon myelin sheath is prone to injury associated with N-methyl-d-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847599/ https://www.ncbi.nlm.nih.gov/pubmed/29531223 http://dx.doi.org/10.1038/s41467-018-03427-1 |
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author | Doyle, Sean Hansen, Daniel Bloch Vella, Jasmine Bond, Peter Harper, Glenn Zammit, Christian Valentino, Mario Fern, Robert |
author_facet | Doyle, Sean Hansen, Daniel Bloch Vella, Jasmine Bond, Peter Harper, Glenn Zammit, Christian Valentino, Mario Fern, Robert |
author_sort | Doyle, Sean |
collection | PubMed |
description | The axon myelin sheath is prone to injury associated with N-methyl-d-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury. |
format | Online Article Text |
id | pubmed-5847599 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58475992018-03-15 Vesicular glutamate release from central axons contributes to myelin damage Doyle, Sean Hansen, Daniel Bloch Vella, Jasmine Bond, Peter Harper, Glenn Zammit, Christian Valentino, Mario Fern, Robert Nat Commun Article The axon myelin sheath is prone to injury associated with N-methyl-d-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury. Nature Publishing Group UK 2018-03-12 /pmc/articles/PMC5847599/ /pubmed/29531223 http://dx.doi.org/10.1038/s41467-018-03427-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Doyle, Sean Hansen, Daniel Bloch Vella, Jasmine Bond, Peter Harper, Glenn Zammit, Christian Valentino, Mario Fern, Robert Vesicular glutamate release from central axons contributes to myelin damage |
title | Vesicular glutamate release from central axons contributes to myelin damage |
title_full | Vesicular glutamate release from central axons contributes to myelin damage |
title_fullStr | Vesicular glutamate release from central axons contributes to myelin damage |
title_full_unstemmed | Vesicular glutamate release from central axons contributes to myelin damage |
title_short | Vesicular glutamate release from central axons contributes to myelin damage |
title_sort | vesicular glutamate release from central axons contributes to myelin damage |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847599/ https://www.ncbi.nlm.nih.gov/pubmed/29531223 http://dx.doi.org/10.1038/s41467-018-03427-1 |
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