Microglial cells are critical components of the injurious cascade in a large number of neurodegenerative diseases. However, the precise molecular mechanisms by which microglia mediate neuronal cell death have not been fully delineated. We report here that reactive species released from activated microglia induce the liberation of Zn2+ from intracellular stores in cultured cortical neurons, with a subsequent enhancement in neuronal voltage-gated K+ currents, two events that have been intimately linked to apoptosis. Both the intraneuronal Zn2+ release and the K+ current surge could be prevented by the NADPH oxidase inhibitor apocynin, the free radical scavenging mixture of superoxide dismutase and catalase, as well as by 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride. The enhancement of K+ currents was prevented by neuronal overexpression of metallothionein III or by expression of a dominant negative (DN) vector for the upstream mitogen-activated protein kinase apoptosis signal regulating kinase-1 (ASK-1). Importantly, neurons overexpressing metallothionein-Ill or transfected with DN vectors for ASK-1 or Kv2.1-encoded K+ channels were resistant to microglial-induced toxicity. These results establish a direct link between microglial-generated oxygen and nitrogen reactive products and neuronal cell death mediated by intracellular Zn2+ release and a surge in K+ currents. (c) 2007 Wiley-Liss, Inc.