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Cytosolic phospholipase A2α (cPLA2α) is implicated in the progression of excitotoxic neuronal injury and cerebral ischemia. Previous work suggests that cPLA2α increases aberrant electrophysiologic events through attenuating K+ channel functions. Nevertheless, which K+ channels are affected by cPLA2α needs to be determined. Here we examined K+ channels-mediated electrophysiologic responses in hippocampal CA1 pyramidal neurons from wild-type and cPLA2α−/− mice using simultaneous patch-clamp recording and confocal Ca2+ imaging. After the exposure to the blockers of Ca2+-sensitive and A-type K+ channels, all CA1 neurons developed spike broadening and increased dendritic Ca2+ transients. These effects were occluded in CA1 neurons from cPLA2α−/− mice. Therefore, cPLA2α modulates the functions of Ca2+-sensitive and A-type K+ channels in neurotoxicity.