1. Department of Physiology, University College London, Gower Street, London WC1E 6BT, UK
2. Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, PO Box 1105, Blindern, N-0317 Oslo, Norway

Correspondence to: David Attwell¹ Correspondence and requests for materials should be addressed to D.A. (Email: D.Attwell@ucl.ac.uk).

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 stroke^{1, 2, 3, 4}. Unlike neurons⁵, white matter oligodendrocytes reportedly lack NMDA (N-methyl-d-aspartate) receptors^{6, 7}. It is believed that glutamate damages oligodendrocytes, especially their precursor cells, by acting on calcium-permeable AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptors alone^{1, 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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