Vesicular glutamate release from central axons contributes to myelin damage

Sean Doyle, Daniel Bloch Hansen, Jasmine Vella, Peter Bond, Glenn Harper, Christian Zammit, Mario Valentino and Robert Fern ()
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Sean Doyle: University of Plymouth
Daniel Bloch Hansen: University of Plymouth
Jasmine Vella: University of Malta
Peter Bond: University of Plymouth
Glenn Harper: University of Plymouth
Christian Zammit: University of Malta
Mario Valentino: University of Malta
Robert Fern: University of Plymouth

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03427-1

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