Rapid Ischemic Cell Death in Immature Oligodendrocytes: A Fatal Glutamate Release Feedback Loop

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Abstract
Ischemic injury of immature oligodendrocytes is a major component of the brain injury associated with cerebral palsy, the most common human birth disorder. We now report that cultured immature oligodendrocytes [O4+/galactoceramide (GC)−] are exquisitely sensitive to ischemic injury (80% of cells were dead after 25.5 min of oxygen and glucose withdrawal). This rapid ischemic cell death was mediated by Ca2+influx via non-NMDA glutamate receptors. The receptors were gated by the release of glutamate from the immature oligodendrocytes themselves via reverse glutamate transport and included a significant element of autologous feedback of glutamate from cells onto their own receptors. High (≥100 μm) extracellular glutamate was protective against ischemic injury as a result of non-NMDA glutamate receptor desensitization. Other potential pathways of Ca2+influx, such as voltage-gated Ca2+channels, NMDA receptors, or the Na+–Ca2+exchanger, did not significantly contribute to ischemic Ca2+influx or cell injury. Release of Ca2+from intracellular stores was also not an important factor. In agreement with previous studies, more mature oligodendrocytes (O4−/GC+) were found to be less sensitive to ischemic injury than were the immature cells studied here.