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Article: Intracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia

TitleIntracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date2009
PublisherSociety for Neuroscience. The Journal's web site is located at http://www.jneurosci.org
Citation
Journal of Neuroscience, 2009, v. 29 n. 4, p. 1105-1114 How to Cite?
AbstractDespite 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. Copyright © 2009 Society for Neuroscience.
Persistent Identifierhttp://hdl.handle.net/10722/90826
ISSN
2015 Impact Factor: 5.924
2015 SCImago Journal Rankings: 5.105
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthT32 NS45540
NS36548
NS051288
Funding Information:

This work was supported by National Institutes of Health Grants T32 NS45540 (Y.V.M.), NS36548 (J.H.W.), and NS051288 (C. W. S.). We thank Robert Dietz for performing initial experiments testing the effects of TPEN on Rh123 fluorescence signals and Thomas Vander Jagt for initial fura-6F/FluoZin-3 measurements during OGD, which motivated the studies described in this manuscript. We also thank Stefano Sensi for productive discussions.

References

 

DC FieldValueLanguage
dc.contributor.authorMedvedeva, YVen_HK
dc.contributor.authorLin, Ben_HK
dc.contributor.authorShuttleworth, CWen_HK
dc.contributor.authorWeiss, JHen_HK
dc.date.accessioned2010-09-17T10:08:58Z-
dc.date.available2010-09-17T10:08:58Z-
dc.date.issued2009en_HK
dc.identifier.citationJournal of Neuroscience, 2009, v. 29 n. 4, p. 1105-1114en_HK
dc.identifier.issn0270-6474en_HK
dc.identifier.urihttp://hdl.handle.net/10722/90826-
dc.description.abstractDespite 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. Copyright © 2009 Society for Neuroscience.en_HK
dc.languageengen_HK
dc.publisherSociety for Neuroscience. The Journal's web site is located at http://www.jneurosci.orgen_HK
dc.relation.ispartofJournal of Neuroscienceen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.titleIntracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemiaen_HK
dc.typeArticleen_HK
dc.identifier.emailLin, B:blin@hku.hken_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1523/JNEUROSCI.4604-08.2009en_HK
dc.identifier.pmid19176819-
dc.identifier.pmcidPMC2637403-
dc.identifier.scopuseid_2-s2.0-59649092943en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-59649092943&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume29en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1105en_HK
dc.identifier.epage1114en_HK
dc.identifier.isiWOS:000262859000022-

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