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The Journal of Neuroscience, June 15, 2001, 21(12):4237-4248

AMPA/Kainate Receptor Activation Mediates Hypoxic Oligodendrocyte Death and Axonal Injury in Cerebral White Matter

Selva Baltan Tekkök and Mark P. Goldberg

Department of Neurology, Center for the Study of Nervous System Injury, Washington University, St. Louis, Missouri 63110-1193

We developed an in situ model to investigate the hypothesis that AMPA/kainate (AMPA/KA) receptor activation contributes to hypoxic-ischemic white matter injury in the adult brain. Acute coronal brain slices, including corpus callosum, were prepared from adult mice. After exposure to transient oxygen and glucose deprivation (OGD), white matter injury was assessed by electrophysiology and immunofluorescence for oligodendrocytes and axonal neurofilaments. White matter cellular components and the stimulus-evoked compound action potential (CAP) remained stable for 12 hr after preparation. OGD for 30 min resulted in an irreversible loss of the CAP as well as structural disruption of axons and subsequent loss of neurofilament immunofluorescence. OGD also caused widespread oligodendrocyte death, demonstrated by the loss of APC labeling and the gain of pyknotic nuclear morphology and propidium iodide labeling. Blockade of AMPA/KA receptors with 30 µM NBQX or the AMPA-selective antagonist 30 µM GYKI 52466 prevented OGD-induced oligodendrocyte death. Oligodendrocytes also were preserved by the removal of Ca2+, but not by a blockade of voltage-gated Na+ channels. The protective action of NBQX was still present in isolated corpus callosum slices. CAP areas and axonal structure were preserved by Ca2+ removal and partially protected by a blockade of voltage-gated Na+ channels. NBQX prevented OGD-induced CAP loss and preserved axonal structure. These observations highlight convergent pathways leading to hypoxic-ischemic damage of cerebral white matter. In accordance with previous suggestions, the activation of voltage-gated Na+ channels contributes to axonal damage. Overactivation of glial AMPA/KA receptors leads to oligodendrocyte death and also plays an important role in structural and functional disruption of axons.

Key words: oligodendrocyte; white matter injury; AMPA/kainate receptors; axonal injury; brain slices; compound action potential; ischemia; glutamate

Copyright © 2001 Society for Neuroscience  0270-6474/01/21124237-12$05.00/0




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