Pathologies such as cerebral palsy, spinal cord injury and multiple sclerosis involve glutamate-mediated damage to the white matter. We have recently shown that oligodendrocytes in the white matter of the cerebellum and corpus callosum express NMDA receptors, which are activated during ischaemic conditions (Káradóttir et al. 2005). Thus, as in neurons, these receptors may cause cell damage by glutamate-induced excitotoxicity. The aim of this study was to investigate further the properties of oligodendrocyte NMDA receptors, using whole-cell voltage-clamp recordings in situ in rat brain slices. Mature oligodendrocytes were whole-cell clamped with internal solution containing Cs+ as the main cation and identified by their morphology as visualized by dye filling (Káradóttir et al. 2005). The peak current response evoked at -60mV by repetitive NMDA applications (60μM, once every ten minutes) exhibited a rundown, both in the corpus callosum and cerebellum. This rundown was area-dependent: in cerebellum the response to the third NMDA application was 33±5% (mean±s.e.m., n=13 cells) smaller than the first response, whereas in the corpus callosum it was 79±9% smaller (n=15; significantly different, p=0.0002 by 2-tailed t test). In neurons, NMDA response rundown can be reduced or abolished by lowering the extracellular calcium concentration (Rosenmund & Westbrook, 1993). However, in cerebellar oligodendrocytes, the rundown was larger when we decreased the extracellular calcium concentration from 2.5mM to 0.2mM (in 0.2mM [Ca2+] the response to the third NMDA application was 63±4% (n=8) smaller than the first one; significantly different to 2.5mM [Ca2+], p=0.0002 by 2-tailed t test). NMDA receptor blockers have been widely tested as agents that may prevent grey matter damage in conditions like stroke. The discovery of NMDA receptors in oligodendrocytes (Káradóttir et al. 2005) suggests that these blockers may be useful for treating white matter diseases. Memantine, the only clinically-approved NMDA receptor antagonist, inhibited the NMDA-evoked current in cerebellar oligodendrocytes (IC50=26±7μM, 122 cells). These data suggest that the NMDA receptors (or their downstream signalling) in oligodendrocytes differ from those in neurons and differ between white matter areas. Memantine or related compounds might be useful as a therapy for preventing white matter damage.
University College London 2006 (2006) Proc Physiol Soc 3, C109
Oral Communications: Rundown and inhibition of oligodendrocyte NMDA receptors
Yamina Bakiri1, Nicola B Hamilton1, Ragnhildur Káradóttir1, David Attwell1
1. Physiology, UCL, London, United Kingdom.
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Where applicable, experiments conform with Society ethical requirements.