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The Journal of Neuroscience, February 15, 2002, 22(4):1273-1279

Blockade of Ca²⁺-Permeable AMPA/Kainate Channels Decreases Oxygen-Glucose Deprivation-Induced Zn²⁺ Accumulation and Neuronal Loss in Hippocampal Pyramidal Neurons

Hong Z. Yin¹, Stefano L. Sensi^{1, 4}, Fumio Ogoshi², and John H. Weiss^{1, 2, 3}

Departments of ¹ Neurology, ² Anatomy and Neurobiology, and ³ Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4292, and ⁴ Department of Neurology, University G. d'Annunzio, Chieti 66013, Italy

Synaptic release of Zn²⁺ and its translocation into postsynaptic neurons probably contribute to neuronal injury after ischemia or epilepsy. Studies in cultured neurons have revealed that of the three major routes of divalent cation entry, NMDA channels, voltage-sensitive Ca²⁺ channels (VSCCs), and Ca²⁺-permeable AMPA/kainate (Ca-A/K) channels, Ca-A/K channels exhibit the highest permeability to exogenously applied Zn²⁺. However, routes through which synaptically released Zn²⁺ gains entry to postsynaptic neurons have not been characterized in vivo. To model ischemia-induced Zn²⁺ movement in a system approximating the in vivo situation, we subjected mouse hippocampal slice preparations to controlled periods of oxygen and glucose deprivation (OGD). Timm's staining revealed little reactive Zn²⁺ in CA1 and CA3 pyramidal neurons of slices exposed in the presence of O₂ and glucose. However, 15 min of OGD resulted in marked labeling in both regions. Whereas strong Zn²⁺ labeling persisted if both the NMDA antagonist MK-801 and the VSCC blocker Gd³⁺ were present during OGD, the presence of either the Ca-A/K channel blocker 1-naphthyl acetyl spermine (NAS) or the extracellular Zn²⁺ chelator Ca²⁺ EDTA substantially decreased Zn²⁺ accumulation in pyramidal neurons of both subregions. In parallel experiments, slices were subjected to 5 min OGD exposures as described above, followed 4 hr later by staining with the cell-death marker propidium iodide. As in the Timm's staining experiments, substantial CA1 or CA3 pyramidal neuronal damage occurred despite the presence of MK-801 and Gd³⁺, whereas injury was decreased by NAS or by Ca²⁺ EDTA (in CA1).

Key words: zinc; ischemia; glutamate; AMPA; naphthyl acetyl spermine; Timm's stain; pyramidal neuron; neurotoxicity; hippocampal slice

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2241273-07$05.00/0

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