Intracellular Zn2+ accumulation enhances suppression of synaptic activity following spreading depolarization

J Neurochem. 2013 Jun;125(5):673-84. doi: 10.1111/jnc.12237. Epub 2013 Apr 16.

Abstract

Spreading depolarization (SD) is a feed-forward wave that propagates slowly throughout brain tissue and recovery from SD involves substantial metabolic demand. Presynaptic Zn(2+) release and intracellular accumulation occurs with SD, and elevated intracellular Zn(2+) ([Zn(2+) ]i ) can impair cellular metabolism through multiple pathways. We tested here whether increased [Zn(2+) ]i could exacerbate the metabolic challenge of SD, induced by KCl, and delay recovery in acute murine hippocampal slices. [Zn(2+) ]i loading prior to SD, by transient ZnCl2 application with the Zn(2+) ionophore pyrithione (Zn/Pyr), delayed recovery of field excitatory post-synaptic potentials (fEPSPs) in a concentration-dependent manner, prolonged DC shifts, and significantly increased extracellular adenosine accumulation. These effects could be due to metabolic inhibition, occurring downstream of pyruvate utilization. Prolonged [Zn(2+) ]i accumulation prior to SD was required for effects on fEPSP recovery and consistent with this, endogenous synaptic Zn(2+) release during SD propagation did not delay recovery from SD. The effects of exogenous [Zn(2+) ]i loading were also lost in slices preconditioned with repetitive SDs, implying a rapid adaptation. Together, these results suggest that [Zn(2+) ]i loading prior to SD can provide significant additional challenge to brain tissue, and could contribute to deleterious effects of [Zn(2+) ]i accumulation in a range of brain injury models.

Publication types

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

MeSH terms

  • Animals
  • Chlorides / metabolism*
  • Cortical Spreading Depression / physiology*
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Hippocampus / metabolism
  • Intracellular Fluid / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Synapses / metabolism*
  • Up-Regulation / physiology*
  • Zinc Compounds / metabolism*

Substances

  • Chlorides
  • Zinc Compounds
  • zinc chloride