NMDA receptors are expressed in oligodendrocytes and activated in ischaemia

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Volpe, J. J. Neurobiology of periventricular leukomalacia in the premature infant. Pediatr. Res. 50, 553–562 (2001)

    CAS  Article  Google Scholar 

  2. 2

    Stys, P. K. White matter injury mechanisms. Curr. Mol. Med. 4, 113–130 (2004)

    CAS  Article  Google Scholar 

  3. 3

    Matute, C. et al. The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends Neurosci. 24, 224–230 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Dewar, D., Underhill, S. M. & Goldberg, M. P. Oligodendrocytes and ischemic brain injury. J. Cereb. Blood Flow Metab. 23, 263–274 (2003)

    Article  Google Scholar 

  5. 5

    Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634 (1988)

    CAS  Article  Google Scholar 

  6. 6

    Patneau, D. K., Wright, P. W., Winters, C., Mayer, M. L. & Gallo, V. Glial cells of the oligodendrocyte lineage express both kainate- and AMPA-preferring subtypes of glutamate receptor. Neuron 12, 357–371 (1994)

    CAS  Article  Google Scholar 

  7. 7

    Berger, T., Walz, W., Schnitzer, J. & Kettenmann, H. GABA- and glutamate-activated currents in glial cells of the mouse corpus callosum slice. J. Neurosci. Res. 31, 21–27 (1992)

    CAS  Article  Google Scholar 

  8. 8

    Oka, A., Belliveau, M. J., Rosenberg, P. A. & Volpe, J. J. Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J. Neurosci. 13, 1441–1453 (1993)

    CAS  Article  Google Scholar 

  9. 9

    Follett, P. L., Rosenberg, P. A., Volpe, J. J. & Jensen, F. E. NBQX attenuates excitotoxic injury in developing white matter. J. Neurosci. 20, 9235–9241 (2000)

    CAS  Article  Google Scholar 

  10. 10

    Tekkök, S. B. & Goldberg, M. P. AMPA/kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter. J. Neurosci. 21, 4237–4248 (2001)

    Article  Google Scholar 

  11. 11

    Agrawal, S. K. & Fehlings, M. G. Role of NMDA and non-NMDA ionotropic glutamate receptors in traumatic spinal cord axonal injury. J. Neurosci. 17, 1055–1063 (1997)

    CAS  Article  Google Scholar 

  12. 12

    Wrathall, J. R., Teng, Y. D. & Marriott, R. Delayed antagonism of AMPA/kainate receptors reduces long-term functional deficits resulting from spinal cord trauma. Exp. Neurol. 145, 565–573 (1997)

    CAS  Article  Google Scholar 

  13. 13

    Pitt, D., Werner, P. & Raine, C. S. Glutamate excitotoxicity in a model of multiple sclerosis. Nature Med. 6, 67–70 (2000)

    CAS  Article  Google Scholar 

  14. 14

    Smith, T., Groom, A., Zhu, B. & Turski, L. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nature Med. 6, 62–66 (2000)

    CAS  Article  Google Scholar 

  15. 15

    Wang, C. et al. Functional N-methyl-d-aspartate receptors in O–2A glial precursor cells: a critical role in regulating polysialic acid-neural cell adhesion molecule expression and cell migration. J. Cell Biol. 135, 1565–1581 (1996)

    CAS  Article  Google Scholar 

  16. 16

    Ziak, D., Chvatal, A. & Sykova, E. Glutamate, kainate and NMDA-evoked membrane currents in identified glial cells in rat spinal cord slice. Physiol. Res. 47, 365–375 (1998)

    CAS  PubMed  Google Scholar 

  17. 17

    Schäbitz, W.-R., Li, F. & Fisher, M. The N-methyl-d-aspartate antagonist CNS 1102 protects cerebral gray and white matter from ischemic injury following temporary focal ischemia in rats. Stroke 31, 1709–1714 (2000)

    Article  Google Scholar 

  18. 18

    Wallström, E. et al. Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. J. Neurol. Sci. 137, 89–96 (1996)

    Article  Google Scholar 

  19. 19

    Back, S. A. et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 21, 1302–1312 (2001)

    CAS  Article  Google Scholar 

  20. 20

    Bergles, D. E., Roberts, J. D. B., Somogyi, P. & Jahr, C. E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Kirson, E. D., Schirra, C., Konnerth, A. & Yaari, Y. Early postnatal switch in magnesium sensitivity of NMDA receptors in rat CA1 pyramidal cells. J. Physiol. (Lond.) 521, 99–111 (1999)

    CAS  Article  Google Scholar 

  22. 22

    Kuner, T. & Schoepfer, R. Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels. J. Neurosci. 16, 3549–3558 (1996)

    CAS  Article  Google Scholar 

  23. 23

    Sasaki, Y. F. et al. Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J. Neurophysiol. 87, 2052–2063 (2002)

    CAS  Article  Google Scholar 

  24. 24

    Borges, K. & Kettenmann, H. Blockade of K+ channels induced by AMPA/kainate receptor activation in mouse oligodendrocyte precursor cells is mediated by Na+ entry. J. Neurosci. Res. 42, 579–593 (1995)

    CAS  Article  Google Scholar 

  25. 25

    Allen, N. J., Káradóttir, R. & Attwell, D. A preferential role for glycolysis in preventing the anoxic depolarization of rat hippocampal area CA1 pyramidal cells. J. Neurosci. 25, 848–859 (2005)

    CAS  Article  Google Scholar 

  26. 26

    Yuan, X., Eisen, A. M., McBain, C. J. & Gallo, V. A role for glutamate and its receptors in the regulation of oligodendrocyte development in cerebellar tissue slices. Development 125, 2901–2914 (1998)

    CAS  PubMed  Google Scholar 

  27. 27

    Salter, M. G. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature doi:10.1038/nature04301 (this issue)

  28. 28

    Berry, M., Hubbard, P. & Butt, A. M. Cytology and lineage of NG2-positive glia. J. Neurocytol. 31, 457–467 (2002)

    CAS  Article  Google Scholar 

  29. 29

    Chittajulu, R., Aguirre, A. & Gallo, V. NG2-positive cells in the mouse white and grey matter display distinct physiological properties. J. Physiol. (Lond.) 561, 109–122 (2004)

    Article  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to David Attwell.

Ethics declarations

Competing interests

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

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing