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The Journal of Neuroscience, January 28, 2009, 29(4):1105-1114; doi:10.1523/JNEUROSCI.4604-08.2009

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Neurobiology of Disease
Intracellular Zn²⁺ Accumulation Contributes to Synaptic Failure, Mitochondrial Depolarization, and Cell Death in an Acute Slice Oxygen–Glucose Deprivation Model of Ischemia

Yuliya V. Medvedeva,^1,2 Bin Lin,¹ C. William Shuttleworth,³ and John H. Weiss^1,2

Departments of ¹Neurology and ²Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697, and ³Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131

Correspondence should be addressed to Dr. John H. Weiss, Department of Neurology, University of California, Irvine, Irvine, CA 92697-4292. Email: jweiss{at}uci.edu

Despite considerable evidence for contributions of both Zn²⁺ and Ca²⁺ in ischemic brain damage, the relative importance of each cation to very early events in injury cascades is not well known. We examined Ca²⁺ and Zn²⁺ dynamics in hippocampal slices subjected to oxygen–glucose deprivation (OGD). When single CA1 pyramidal neurons were loaded via a patch pipette with a Ca²⁺-sensitive indicator (fura-6F) and an ion-insensitive indicator (AlexaFluor-488), small dendritic fura-6F signals were noted after several (6–8) minutes of OGD, followed shortly by sharp somatic signals, which were attributed to Ca²⁺ ("Ca²⁺ deregulation"). At close to the time of Ca²⁺ deregulation, neurons underwent a terminal increase in plasma membrane permeability, indicated by loss of AlexaFluor-488 fluorescence. In neurons coloaded with fura-6F and a Zn²⁺-selective indicator (FluoZin-3), progressive rises in cytosolic Zn²⁺ levels were detected before Ca²⁺ deregulation. Addition of the Zn²⁺ chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) significantly delayed both Ca²⁺ deregulation and the plasma membrane permeability increases, indicating that Zn²⁺ contributes to the degenerative signaling. Present observations further indicate that Zn²⁺ is rapidly taken up into mitochondria, contributing to their early depolarization. Also, TPEN facilitated recovery of the mitochondrial membrane potential and of field EPSPs after transient OGD, and combined removal of Ca²⁺ and Zn²⁺ markedly extended the duration of OGD tolerated. These data provide new clues that Zn²⁺ accumulates rapidly in neurons during slice OGD, is taken up by mitochondria, and contributes to consequent mitochondrial dysfunction, cessation of synaptic transmission, Ca²⁺ deregulation, and cell death.

Key words: hippocampal slice; mitochondria; zinc; calcium; Ca²⁺; ischemia

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Received Sept. 24, 2008; revised Nov. 27, 2008; accepted Dec. 7, 2008.

Correspondence should be addressed to Dr. John H. Weiss, Department of Neurology, University of California, Irvine, Irvine, CA 92697-4292. Email: jweiss{at}uci.edu

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