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

<jats:p>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<jats:sup>+</jats:sup>/galactoceramide (GC)<jats:sup>−</jats:sup>] 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 Ca<jats:sup>2+</jats:sup>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 μ<jats:sc>m</jats:sc>) extracellular glutamate was protective against ischemic injury as a result of non-NMDA glutamate receptor desensitization. Other potential pathways of Ca<jats:sup>2+</jats:sup>influx, such as voltage-gated Ca<jats:sup>2+</jats:sup>channels, NMDA receptors, or the Na<jats:sup>+</jats:sup>–Ca<jats:sup>2+</jats:sup>exchanger, did not significantly contribute to ischemic Ca<jats:sup>2+</jats:sup>influx or cell injury. Release of Ca<jats:sup>2+</jats:sup>from intracellular stores was also not an important factor. In agreement with previous studies, more mature oligodendrocytes (O4<jats:sup>−</jats:sup>/GC<jats:sup>+</jats:sup>) were found to be less sensitive to ischemic injury than were the immature cells studied here.</jats:p>