Astrocytes Are More Resistant Than Neurons to the Cytotoxic Effects of Increased [Zn2+

Abstract

Increased intracellular free Zn2+ ([Zn2+]i) is toxic to neurons. Glia are more resistant to Zn2+-mediated toxicity; however, it is not known if this is because glia are less permeable to Zn2+ or if glia possess intrinsic mechanisms that serve to buffer or extrude excess [Zn2+]i. We used the Zn2+-selective ionophore pyrithione to directly increase [Zn2+]i in both neurons and astrocytes. In neurons, a 5-min exposure to 1 μM extracellular Zn2+ in combination with pyrithione produced widespread toxicity, whereas extensive astrocyte injury was not observed until extracellular Zn2+ was increased to 10 μM. Measurements with magfura-2 demonstrated that pyrithione increased [Zn2+]i to similar levels in both cell types. We also measured how increased [Zn2+]i affects mitochondrial membrane potential (Δψm). In astrocytes, but not in neurons, toxic [Zn2+]i resulted in an acute loss of Δψm, suggesting that mitochondrial dysregulation may be an early event in [Zn2+]i-induced astrocyte but not neuronal death.