Spreading depression and related events are significant sources of neuronal Zn2+ release and accumulation

J Cereb Blood Flow Metab. 2011 Apr;31(4):1073-84. doi: 10.1038/jcbfm.2010.183. Epub 2010 Oct 27.

Abstract

Spreading depression (SD) involves coordinated depolarizations of neurons and glia that propagate through the brain tissue. Repetitive SD-like events are common following human ischemic strokes, and are believed to contribute to the enlargement of infarct volume. Accumulation of Zn(2+) is also implicated in ischemic neuronal injury. Synaptic glutamate release contributes to SD propagation, and because Zn(2+) is costored with glutamate in some synaptic vesicles, we examined whether Zn(2+) is released by SD and may therefore provide a significant source of Zn(2+) in the postischemic period. Spreading depression-like events were generated in acutely prepared murine hippocampal slices by deprivation of oxygen and glucose (OGD), and Zn(2+) release was detected extracellularly by a Zn(2+)-selective indicator FluoZin-3. Deprivation of oxygen and glucose-SD produced large FluoZin-3 increases that propagated with the event, and signals were abolished in tissues from ZnT3 knockout animals lacking synaptic Zn(2+). Synaptic Zn(2+) release was also maintained with repetitive SDs generated by microinjections of KCl under normoxic conditions. Intracellular Zn(2+) accumulation in CA1 neurons, assessed using microinjection of FluoZin-3, showed significant increases following SD that was attributed to synaptic Zn(2+) release. These results suggest that Zn(2+) is released during SDs and could provide a significant source of Zn(2+) that contributes to neurodegeneration in the postischemic period.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Ischemia / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cation Transport Proteins
  • Chelating Agents / pharmacology
  • Cortical Spreading Depression / physiology*
  • Edetic Acid / pharmacology
  • Fluorescent Dyes
  • Glucose / deficiency
  • Hypoxia, Brain / pathology
  • Indicators and Reagents
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism*
  • Polycyclic Compounds
  • Potassium Chloride / pharmacology
  • Pyramidal Cells / metabolism
  • Zinc / metabolism*

Substances

  • Carrier Proteins
  • Cation Transport Proteins
  • Chelating Agents
  • FluoZin-3
  • Fluorescent Dyes
  • Indicators and Reagents
  • Membrane Proteins
  • Membrane Transport Proteins
  • Polycyclic Compounds
  • Slc30a3 protein, mouse
  • Potassium Chloride
  • Edetic Acid
  • Glucose
  • Zinc