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The Journal of Neuroscience, January 1, 2000, 20(1):34-42

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

Robert Fern and Thomas Möller

Department of Neurology, University of Washington, Seattle, Washington 98195

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.

Key words: Ca²⁺; cell death; cerebral palsy; ischemia; glia; glutamate transport; neonatal brain injury; necrotic cell death; non-NMDA glutamate receptor; oligodendrocyte; white matter

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Copyright © 2000 Society for Neuroscience  0270-6474/0/20134-09$05.00/0

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