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.
Subscribe to Journal
Get full journal access for 1 year
only $3.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Volpe, J. J. Neurobiology of periventricular leukomalacia in the premature infant. Pediatr. Res. 50, 553–562 (2001)
Stys, P. K. White matter injury mechanisms. Curr. Mol. Med. 4, 113–130 (2004)
Matute, C. et al. The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends Neurosci. 24, 224–230 (2001)
Dewar, D., Underhill, S. M. & Goldberg, M. P. Oligodendrocytes and ischemic brain injury. J. Cereb. Blood Flow Metab. 23, 263–274 (2003)
Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634 (1988)
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)
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)
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)
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)
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)
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)
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)
Pitt, D., Werner, P. & Raine, C. S. Glutamate excitotoxicity in a model of multiple sclerosis. Nature Med. 6, 67–70 (2000)
Smith, T., Groom, A., Zhu, B. & Turski, L. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nature Med. 6, 62–66 (2000)
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)
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)
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)
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)
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)
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)
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)
Kuner, T. & Schoepfer, R. Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels. J. Neurosci. 16, 3549–3558 (1996)
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)
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)
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)
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)
Salter, M. G. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature doi:10.1038/nature04301 (this issue)
Berry, M., Hubbard, P. & Butt, A. M. Cytology and lineage of NG2-positive glia. J. Neurocytol. 31, 457–467 (2002)
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)
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.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
This file contains details of additional methods used in this study, Supplementary Figure Legends and additional references. (DOC 37 kb)
Effect of TTX (1µM) and TBOA (200µM) on glutamate (100µM) evoked current in a mature cell. (PDF 513 kb)
Controls for antibody labelling in the white matter of cerebellar slices. (PDF 4193 kb)
Colocalization of NR3 and NR2C subunits in the myelinating processes of mature cerebellar oligodendrocytes. (PDF 588 kb)
Colocalization of NR1 and NR2C subunits in myelinating processes and around the soma of cerebellar oligodendrocytes. (PDF 385 kb)
NR1 immunogold labelling. (PDF 3068 kb)
Images of Lucifer fill of a recorded oligodendrocyte (PDF 5278 kb)
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
Neural Regeneration Research (2021)
Neuroscience and Behavioral Physiology (2020)
Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis
Frontiers in Neurology (2020)
Mir363-3p Treatment Attenuates Long-Term Cognitive Deficits Precipitated by an Ischemic Stroke in Middle-Aged Female Rats
Frontiers in Aging Neuroscience (2020)