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NMDA receptors are expressed in oligodendrocytes and activated in ischaemia

Nature volume 438, pages 1162–1166 (2005)Cite this article

Abstract

Glutamate-mediated damage to oligodendrocytes contributes to mental or physical impairment in periventricular leukomalacia (pre- or perinatal white matter injury leading to cerebral palsy), spinal cord injury, multiple sclerosis and stroke1,2,3,4. Unlike neurons5, white matter oligodendrocytes reportedly lack NMDA (N-methyl-d-aspartate) receptors6,7. It is believed that glutamate damages oligodendrocytes, especially their precursor cells, by acting on calcium-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptors alone1,2,3,4 or by reversing cystine–glutamate exchange and depriving cells of antioxidant protection8. Here we show that precursor, immature and mature oligodendrocytes in the white matter of the cerebellum and corpus callosum exhibit NMDA-evoked currents, mediated by receptors that are blocked only weakly by Mg2+ and that may contain NR1, NR2C and NR3 NMDA receptor subunits. NMDA receptors are present in the myelinating processes of oligodendrocytes, where the small intracellular space could lead to a large rise in intracellular ion concentration in response to NMDA receptor activation. Simulating ischaemia led to development of an inward current in oligodendrocytes, which was partly mediated by NMDA receptors. These results point to NMDA receptors of unusual subunit composition as a potential therapeutic target for preventing white matter damage in a variety of diseases.

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Figure 1: Glutamate-evoked current in oligodendrocytes.
Figure 2: Oligodendrocyte NMDA receptors show weak Mg 2+ -block.
Figure 3: Oligodendrocyte NMDA receptors.
Figure 4: Ischaemia activates NMDA receptors.

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Acknowledgements

We thank D. Rowitch, C. D. Stiles and J. Alberta for Olig2 antibody, F. A. Stephenson, R. J. Wenthold and O. P. Ottersen for NR1 antibody, and A. Gibb, K. Jessen, R. Mirsky, W. Richardson, D. Rossi, J. Rothman, A. Silver and J. Storm-Mathisen for advice. This work was supported by the Wellcome Trust, the European Union, the Norwegian Research Council and a Wolfson-Royal Society Award. R.K. was in the 4-year PhD Programme in Neuroscience at UCL.

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Authors and Affiliations

  1. Department of Physiology, University College London, Gower Street, WC1E 6BT, London, UK

    Ragnhildur Káradóttir, Pauline Cavelier & David Attwell

  2. Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, PO Box 1105, Blindern, N-0317, Oslo, Norway

    Linda H. Bergersen

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  1. Ragnhildur Káradóttir
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Correspondence to David Attwell.

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Supplementary information

Supplementary Methods

This file contains details of additional methods used in this study, Supplementary Figure Legends and additional references. (DOC 37 kb)

Supplementary Figure 1

Effect of TTX (1µM) and TBOA (200µM) on glutamate (100µM) evoked current in a mature cell. (PDF 513 kb)

Supplementary Figure 2

Controls for antibody labelling in the white matter of cerebellar slices. (PDF 4193 kb)

Supplementary Figure 3

Colocalization of NR3 and NR2C subunits in the myelinating processes of mature cerebellar oligodendrocytes. (PDF 588 kb)

Supplementary Figure 4

Colocalization of NR1 and NR2C subunits in myelinating processes and around the soma of cerebellar oligodendrocytes. (PDF 385 kb)

Supplementary Figure 5

NR1 immunogold labelling. (PDF 3068 kb)

Supplementary Figure 6

Images of Lucifer fill of a recorded oligodendrocyte (PDF 5278 kb)

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Káradóttir, R., Cavelier, P., Bergersen, L. et al. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438, 1162–1166 (2005). https://doi.org/10.1038/nature04302

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