TY - JOUR T1 - Zn<sup>2+</sup> Influx Is Critical for Some Forms of Spreading Depression in Brain Slices JF - The Journal of Neuroscience JO - J. Neurosci. SP - 8014 LP - 8024 DO - 10.1523/JNEUROSCI.0765-08.2008 VL - 28 IS - 32 AU - Robert M. Dietz AU - John H. Weiss AU - Claude W. Shuttleworth Y1 - 2008/08/06 UR - http://www.jneurosci.org/content/28/32/8014.abstract N2 - 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. ER -