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The Journal of Neuroscience, August 6, 2008, 28(32):8014-8024; doi:10.1523/JNEUROSCI.0765-08.2008

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Neurobiology of Disease
Zn²⁺ Influx Is Critical for Some Forms of Spreading Depression in Brain Slices

Robert M. Dietz,¹ John H. Weiss,^2,3 and Claude W. Shuttleworth¹

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

Correspondence should be addressed to Dr. Claude W. Shuttleworth, Department of Neurosciences, MSC08 4740, University of New Mexico School of Medicine, 1 University of New Mexico, Albuquerque, NM 87131-0001. Email: bshuttleworth{at}salud.unm.edu

Spreading depression (SD) is wave of profound depolarization that propagates throughout brain tissue and can contribute to the spread of injury after stroke or traumatic insults. The contribution of Ca²⁺ influx to SD differs depending on the stimulus, and we show here that Zn²⁺ can play a critical complementary role in murine hippocampal slices. In initial studies, we used the Na⁺/K⁺ ATPase inhibitor ouabain and found conditions in which SD was always prevented by L-type Ca²⁺ channel blockers; however, Ca²⁺ influx was not responsible for L-type effects. Cytosolic Ca²⁺ increases were not detectable in CA1 neurons before SD, and removal of extracellular Ca²⁺ did not prevent ouabain-SD. In contrast, cytosolic Zn²⁺ increases were observed in CA1 neurons before ouabain-SD, and L-type channel block prevented the intracellular Zn²⁺ rises. A slow mitochondrial depolarization observed before ouabain-SD was abolished by L-type channel block, and Zn²⁺ accumulation contributed substantially to initial mitochondrial depolarizations. Selective chelation of Zn²⁺ with N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) abolished SD, implying that Zn²⁺ entry can play a critical role in the generation of ouabain-SD. TPEN was most effective when synaptic activity was reduced by adenosine A₁ receptor activation, and a combination of Ca²⁺ and Zn²⁺ removal was required to prevent ouabain-SD when A₁ receptors were blocked. Similarly, Zn²⁺ chelation could prevent SD triggered by oxygen/glucose deprivation but Zn²⁺ accumulation did not contribute to SD triggered by localized high K⁺ exposures. These results identify Zn²⁺ as a new target for the block of spreading depolarizations after brain injury.

Key words: hippocampal slice; mitochondria; spreading depression; calcium channels; zinc; ouabain

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Received Oct. 11, 2007; revised June 12, 2008; accepted June 17, 2008.

Correspondence should be addressed to Dr. Claude W. Shuttleworth, Department of Neurosciences, MSC08 4740, University of New Mexico School of Medicine, 1 University of New Mexico, Albuquerque, NM 87131-0001. Email: bshuttleworth{at}salud.unm.edu

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