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The Journal of Neuroscience, April 11, 2007, 27(15):4220-4229; doi:10.1523/JNEUROSCI.5542-06.2007
Neurobiology of Disease
White Matter Axon Vulnerability to AMPA/Kainate Receptor-Mediated Ischemic Injury Is Developmentally Regulated
William J. McCarran1,2 andMark P. Goldberg1,3 1Hope Center for Neurological Disorders and Departments of 2Pediatrics and 3Neurology, Washington University School of Medicine, St. Louis, Missouri 63110
Correspondence should be addressed to Mark P. Goldberg, Department of Neurology, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110-1193. Email: goldbergm{at}neuro.wustl.edu
Periventricular white matter injury (PWMI) is the leading cause of neurodevelopmental morbidity in survivors of premature birth. Cerebral ischemia is considered a major etiologic factor in the generation of PWMI. In adult white matter (WM), ischemic axonal damage is mediated by AMPA/kainate receptors. Mechanisms of ischemic axonal injury during development are not well defined. We used a murine brain slice model to characterize mechanisms of ischemic axonal injury in developing WM. Acute coronal brain slices were prepared from thy1–yellow fluorescent protein (YFP) mice at postnatal day 3 (P3), P7, P10, and P21. Ischemia was simulated by oxygen-glucose deprivation (OGD). YFP-positive axon morphology in the corpus callosum was preserved for at least 15 h under normoxic conditions. OGD resulted in delayed degeneration of YFP-positive axons, characterized by axonal beading, fragmentation, and loss of YFP. AMPA and cyclothiazide damaged WM axons at P7, P10, and P21 but not at P3. The AMPA/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) decreased OGD-induced axonal degeneration and oligodendrocyte loss at P10 and P21. At P3 and P7, NBQX protected oligodendrocytes but did not prevent axonal degeneration after OGD. The NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] provided no protection at any age. These results indicate that developing WM axons are susceptible to ischemic injury. However, mechanisms of axonal degeneration are developmentally regulated. At P3 and P7, corresponding developmentally to the window of peak vulnerability to PWMI in humans, ischemic axonal injury is not mediated by AMPA/kainate receptors. Strategies to protect WM during this period may be substantially different from those used at later developmental stages.
Key words: axon; excitotoxicity; ischemia; oligodendrocyte; periventricular leukomalacia; white matter
Received Sept. 18, 2006; revised Feb. 27, 2007; accepted March 1, 2007.
Correspondence should be addressed to Mark P. Goldberg, Department of Neurology, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110-1193. Email: goldbergm{at}neuro.wustl.edu
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