Synaptic release and extracellular actions of Zn2+ limit propagation of spreading depression and related events in vitro and in vivo

Isamu Aiba, Andrew P. Carlson, Christian T. Sheline, C. William Shuttleworth


Cortical spreading depression (CSD) is a consequence of a slowly propagating wave of neuronal and glial depolarization (spreading depolarization; SD). Massive release of glutamate contributes to SD propagation, and it was recently shown that Zn2+ is also released from synaptic vesicles during SD. The present study examined consequences of extracellular Zn2+ accumulation on the propagation of SD. SD mechanisms were studied first in murine brain slices, using focal KCl applications as stimuli and making electrical and optical recordings in hippocampal area CA1. Elevating extracellular Zn2+ concentrations with exogenous ZnCl2 reduced SD propagation rates. Selective chelation of endogenous Zn2+ (using TPEN or CaEDTA) increased SD propagation rates, and these effects appeared due to chelation of Zn2+ derived from synaptic vesicles. Thus, in tissues where synaptic Zn2+ release was absent [knockout (KO) of vesicular Zn2+ transporter ZnT-3], SD propagation rates were increased, and no additional increase was observed following chelation of endogenous Zn2+ in these tissues. The role of synaptic Zn2+ was then examined on CSD in vivo. ZnT-3 KO animals had higher susceptibility to CSD than wild-type controls as evidenced by significantly higher propagation rates and frequencies. Studies of candidate mechanisms excluded changes in neuronal excitability, presynaptic release, and GABA receptors but left open a possible contribution of N-methyl-d-aspartate (NMDA) receptor inhibition. These results suggest the extracellular accumulation of synaptically released Zn2+ can serve as an intrinsic inhibitor to limit SD events. The inhibitory action of extracellular Zn2+ on SD may counteract to some extent the neurotoxic effects of intracellular Zn2+ accumulation in acute brain injury models.

  • cortical spreading depression
  • zinc
  • CA1
  • ZnT-3
  • NMDA-R
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