Abstract 136: Deleterious Effects of Synaptic Zn2+ in a Murine Distal Middle Cerebral Artery Occlusion Model
Background: Previous work has implicated accumulation of Zn2+ as a contributor to ischemic brain injury, however the sources of toxic Zn2+ accumulation are not fully understood. Previous data report that ICV delivery of a Zn2+ chelator limited mild focal stroke (Neuroscience 115 (2002) 871-8). We have recently demonstrated substantial synaptic Zn2+ release following spreading depolarization (JCBFM 31 (2011) 1073-84), and thus it is possible that repetitive spreading depolarization_ known to occur following stroke_ could be a major source of toxic Zn2+. In the present study, we examined whether synaptic Zn2+ release contributes to neuronal injury in a murine focal stroke model.
Methods The effect of synaptic Zn2+ was assessed using mice lacking synaptic Zn2+, due to genetic deletion of the synaptic vesicle transporter ZnT3 (ZnT3 KO). Wild type C57Bl/6 mice were age and sex matched as controls. Mice were anesthetized with isofluorane and the cortical branch of the right middle cerebral artery was cauterized via a temporal burrhole. A single surgeon performed the occlusions. Body temperature was maintained at 37±0.5oC during the procedure and recovery. Animals were allowed to recover for 1 week before euthanasia. Stroke volume was assessed by Fluoro-Jade staining. Statistical analysis with 2-way ANOVA was used to determine the effects of sex and genotype on stroke volume.
Results: There was no peri- or post-procedural mortality. Infarct was confirmed histologically in all animals. Stroke volume was reduced in the ZnT3 KO mice compared to wild type (mean volume 3.54mm3 versus 8.42mm3 respectively, n=7 for each arm). Only genotype (not sex) had a significant effect on stroke volume by 2-way ANOVA (p=0.0042).
Conclusion: Synaptic Zn2+ release leads to increased stroke volume, likely due to toxic Zn2+accumulation. Therapies targeting synaptic release of Zn2+ or repetitive spreading depolarization events (which cause Zn2+ release) may decrease delayed ischemic injuries.
- © 2012 by American Heart Association, Inc.