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NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury

Abstract

Injury to oligodendrocyte processes, the structures responsible for myelination, is implicated in many forms of brain disorder1,2,3,4. Here we show NMDA (N-methyl-d-aspartate) receptor subunit expression on oligodendrocyte processes, and the presence of NMDA receptor subunit messenger RNA in isolated white matter. NR1, NR2A, NR2B, NR2C, NR2D and NR3A subunits showed clustered expression in cell processes, but NR3B was absent. During modelled ischaemia, NMDA receptor activation resulted in rapid Ca2+-dependent detachment and disintegration of oligodendroglial processes in the white matter of mice expressing green fluorescent protein (GFP) specifically in oligodendrocytes (CNP-GFP mice). This effect occurred at mouse ages corresponding to both the initiation and the conclusion of myelination. NR1 subunits were found mainly in oligodendrocyte processes, whereas AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor subunits were mainly found in the somata. Consistent with this observation, injury to the somata was prevented by blocking AMPA/kainate receptors, and preventing injury to oligodendroglial processes required the blocking of NMDA receptors. The presence of NMDA receptors in oligodendrocyte processes explains why previous studies that have focused on the somata have not detected a role for NMDA receptors in oligodendrocyte injury. These NMDA receptors bestow a high sensitivity to acute injury and represent an important new target for drug development in a variety of brain disorders.

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Figure 1: Ischaemia results in rapid loss of oligodendroglial process.
Figure 2: NMDA receptor activation destroys oligodendrocyte processes.
Figure 3: Oligodendrocytes express NMDA receptors in clusters on cell processes and AMPA/kainate receptors diffusely on somata.
Figure 4: Ischaemia results in rapid loss of oligodendroglial process in P25 optic nerve.

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Acknowledgements

We wish to thank V. Gallo for the gift of CNP-GFP mice, I. Eperon for discussion, J. Alix for immunostaining advice, and N. Alcock for technical assistance with electron microscopy. This work was supported by a grant from the National Institutes of Neurological Disorders and Stroke to R.F.

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Correspondence to Robert Fern.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Ischemia produces rapid extinction of oligodendroglial process. (JPG 101 kb)

Supplementary Figure 2

Supplemental plots of process retention in P10 optic nerve. (JPG 100 kb)

Supplementary Figure 3

Supplemental immunostaining of P10 rat optic nerve. (JPG 124 kb)

Supplementary Figure 4

NR1 presence in axons and optic nerve. (JPG 137 kb)

Supplementary Figure 5

Control antibody staining for Figure 3. (JPG 141 kb)

Supplementary Figure 6

mRNA encoding NR1 is present in optic nerve, a neuron free preparation. (JPG 112 kb)

Supplementary Figure 7

Ischemia produces rapid loss of oligodendroglial process in P25 mouse optic nerve. (JPG 232 kb)

Supplementary Figure 8

Primers for PCR (JPG 113 kb)

Supplementary Figure Legends

Supplementary Figure Legends nature04301-s9.doc Text to accompany the above Supplementary Figures. (DOC 510 kb)

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Salter, M., Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438, 1167–1171 (2005). https://doi.org/10.1038/nature04301

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