Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death. Issue 5 (26th February 2013)

• Record Type: Journal Article
• Authors: Mato, Susana; Sánchez‐Gómez, María Victoria; Bernal‐Chico, Ana; Matute, Carlos
• Is Part Of: Glia. Volume 61:Issue 5(2013:May)
• Page Start: 750
• Page End: 764
• Publication Date: 2013-02-26
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22470
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Dyshomeostasis of cytosolic Zn<sup>2+</sup> is a critical mediator of neuronal damage during excitotoxicity. However, the role of this cation in oligodendrocyte pathophysiology is not well understood. The current study examined the contribution of Zn<sup>2+</sup> deregulation to oligodendrocyte injury mediated by AMPA receptors. Oligodendrocytes loaded with the Zn<sup>2+</sup>‐selective indicator FluoZin‐3 responded to mild stimulation of AMPA receptors with fast cytosolic Zn<sup>2+</sup> rises that resulted from intracellular release, as they were not blocked by the extracellular Zn<sup>2+</sup> chelator Ca‐EDTA. Pharmacological experiments suggested that AMPA‐induced Zn<sup>2+</sup> mobilization depends on cytosolic Ca<sup>2+</sup> accumulation, arises from mitochondria and protein‐bound pools, and is triggered by mechanisms that do not involve the generation of reactive oxygen species. Moreover, intracellular Zn<sup>2+</sup> rises resulting from AMPA receptor activation seem to be promoted by Ca<sup>2+</sup>‐dependent cytosolic acidification. Addition of the cell‐permeable Zn<sup>2+</sup> chelator TPEN significantly reduced mitochondrial membrane depolarization, reactive oxygen species production, and cell death by sub‐maximal activation of AMPA receptors both <italic>in vitro</italic> and <italic>in situ</italic>, suggesting that Zn<sup>2+</sup> deregulation is an important mediator of oligodendrocyte excitotoxicity. These data provide evidence that strategies aimed at maintaining Zn<sup>2+</sup> homeostasis may be useful for the treatment of disorders in which excitotoxicity is an important trigger of oligodendroglial death.</p> </abstract>