Hydrogen peroxide (H₂O₂), a reactive oxygen species, is assumed to have a detrimental effect on neuronal plasticity. Indeed, H₂O₂ suppresses long-term potentiation (LTP) in hippocampal slices of normal rats and wild-type (wt) mice. Transgenic mice overexpressing superoxide dismutase (SOD) 1 (tg-SOD), which maintain high ambient H₂O₂, have also been shown to be impaired in their ability to express hippocampal LTP. Paradoxically, H₂O_2, at a concentration (50 μm) that blocks LTP in wt mice, actually enhanced LTP in slices of 2-month-old tg-SOD mice. H₂O₂-dependent LTP in tg-SOD was blocked by the protein phosphatase calcineurin inhibitor FK506, but not by rapamycin, an FK-binding protein 12 (FKBP12) inhibitor or by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), a serine-kinase inhibitor. Interestingly, wt and tg-SOD mice expressed similar levels of the antioxidant enzyme catalase and similar activity of glutathione peroxidase. An opposite situation was found in 2-year-old mice. Aged wt mice were impaired in LTP in a manner that could be reversed by the addition of H₂O₂. Surprisingly, aged tg-SOD mice exhibited larger LTP than that found in wt mice, but this was now reduced by 50 μm H₂O₂. Both young tg-SOD and aged control mice displayed altered protein phosphatase activity, compared with that of young controls; moreover, FK506 inhibited LTP in old tg-SOD as well as in old wt mice treated with H₂O₂. These data promoted a dual role for H₂O₂ in the regulation of LTP, and proposed that it is mediated by the protein phosphatase calcineurin.