NMDA receptors are expressed in oligodendrocytes and activated in ischaemia

摘要

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^–. Unlike neurons, white matter oligodendrocytes reportedly lack NMDA receptors^, and it is believed that glutamate damages oligodendrocytes, especially their precursor cells, by acting only on calcium-permeable AMPA/kainate receptors^– or by reversing cystine-glutamate exchange and depriving cells of antioxidant protection. We now show that precursor, immature and mature oligodendrocytes in the white matter of the cerebellum and corpus callosum exhibit NMDA evoked currents, mediated by receptors which are blocked only weakly by Mg²⁺, which may contain NR1, NR2C and NR3 subunits. NMDA receptors are present in the myelinating processes of oligodendrocytes, where the small intracellular space could lead to a large rise of intracellular ion concentration in response to NMDA receptor activation. Simulating ischaemia led to an inward current developing in oligodendrocytes, which was partly mediated by NMDA receptors. These results point to NMDA receptors of unusual subunit composition as a novel therapeutic target for preventing white matter damage in a range of diseases.