Elevations of the levels of N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) are associated with myelin loss in the leukodystophies Canavan’s disease and Pelizaeus-Merzbacher-like disease. NAAG and NAA can activate neuronal NMDA receptors, and also act on group II mGluRs. Since NMDA receptors are present on oligodendrocytes [Káradóttir et al. (2005) Nature 438: 1162], we hypothesised that NAA and NAAG may damage oligodendrocytes by activating their NMDA receptors, causing a deleterious Ca2+ infl ux. We show that NAAG, but not NAA, evoked an inward membrane current in cerebellar white matter oligodendrocytes, which was reduced by NMDA receptor block (but not by block of mGluRs). The size of the current evoked by NAAG, relative to that evoked by NMDA, was much smaller in oligodendrocytes than in neurons, and NAAG induced a rise in [Ca2+]i in neurons but not in oligodendrocytes. In addition, a major part of the response in oligodendrocytes, but not in neurons, was blocked by TTX. We conclude that the NAAG-evoked current in oligodendrocytes is a secondary consequence of activating neuronal NMDA receptors and is unlikely to be a major contributor to white matter damage in the leukodystrophies. Supported by the Wellcome Trust and Royal Society.
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