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

Authors

  • Russell E. Carter,

    1. Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
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  • Jessica L. Seidel,

    1. Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
    Current affiliation:
    1. Radiology, Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
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  • Britta E. Lindquist,

    1. Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
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  • Christian T. Sheline,

    1. Department of Ophthalmology and the Neuroscience Center of Excellence LSU, Health Sciences Center, New Orleans, Louisiana, USA
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  • C. William Shuttleworth

    Corresponding author
    1. Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
    • Address correspondence and reprint requests to C. William Shuttleworth, PhD, Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. E-mail: bshuttleworth@salud.unm.edu

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Abstract

Spreading depolarization (SD) is a feed-forward wave that propagates slowly throughout brain tissue and recovery from SD involves substantial metabolic demand. Presynaptic Zn2+ release and intracellular accumulation occurs with SD, and elevated intracellular Zn2+ ([Zn2+]i) can impair cellular metabolism through multiple pathways. We tested here whether increased [Zn2+]i could exacerbate the metabolic challenge of SD, induced by KCl, and delay recovery in acute murine hippocampal slices. [Zn2+]i loading prior to SD, by transient ZnCl2 application with the Zn2+ 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 [Zn2+]i accumulation prior to SD was required for effects on fEPSP recovery and consistent with this, endogenous synaptic Zn2+ release during SD propagation did not delay recovery from SD. The effects of exogenous [Zn2+]i loading were also lost in slices preconditioned with repetitive SDs, implying a rapid adaptation. Together, these results suggest that [Zn2+]i loading prior to SD can provide significant additional challenge to brain tissue, and could contribute to deleterious effects of [Zn2+]i accumulation in a range of brain injury models.

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