NMDA receptors are expressed in oligodendrocytes and activated in ischaemia

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Abstract
Oligodendrocytes are the cells in the white matter of the central nervous system that produce and maintain the myelin sheath that insulates the impulse-carrying axon. They are damaged by the neurotransmitter glutamate in diseases as diverse as cerebral palsy, spinal cord injury, stroke and multiple sclerosis. It has become widely accepted that, unlike neurons which are mainly killed by glutamate acting on NMDA receptors, oligodendrocytes lack these receptors and are killed solely by glutamate acting on AMPA/kainate receptors. This thinking has guided therapeutic strategies, but it seems that the underlying assumption about glutamate receptor types may be wrong. Three papers published this week make a convincing case for the presence of NMDA receptors in oligodendrocytes, and for their involvement in causing damage to the cells in injury and disease. This will refocus attention on NMDA receptors as an important therapeutic target for drugs in a variety of neurological disorders. 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.