Rapid ischemic cell death in immature oligodendrocytes: A fatal glutamate release feedback loop

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.