AMPA/Kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter

We developed an in situ model to investigate the hypothesis that AMPA/kaina te (AMPA/KA) receptor activation contributes to hypoxic-ischemic white matt er 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 electro physiology and immunofluorescence for oligodendrocytes and axonal neurofila ments. White matter cellular components and the stimulus-evoked compound ac tion potential (CAP) remained stable for 12 hr after preparation. OGD for 3 0 min resulted in an irreversible loss of the CAP as well as structural dis ruption of axons and subsequent loss of neurofilament immunofluorescence. O GD also caused widespread oligodendrocyte death, demonstrated by the loss o f APC labeling and the gain of pyknotic nuclear morphology and propidium io dide labeling. Blockade of AMPA/KA receptors with 30 muM NBQX or the AMPA-s elective antagonist 30 mM 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 bloc kade of voltage-gated Na+ channels. NBQX prevented OGD-induced CAP loss and preserved axonal structure. These observations highlight convergent pathwa ys leading to hypoxic-ischemic damage of cerebral white matter. In accordan ce with previous suggestions, the activation of voltage-gated Na+ channels contributes to axonal damage. Overactivation of glial AMPA/KA receptors lea ds to oligodendrocyte death and also plays an important role in structural and functional disruption of axons.