Pharmacological studies have suggested that long-term potentiation (LTP) and long-term depression (LTD) and depotentiation, three forms of synaptic plasticity in the hippocampus, require the activity of the phosphatase calcineurin. At least two different isoforms of calcineurin are found in the central nervous system. To investigate whether all of these forms of synaptic plasticity require the same isoforms of calcineurin, we have examined LTD, depotentiation, and LTP in mice lacking the predominant calcineurin isoform in the central nervous system, Aalpha-/- mice. Depotentiation was abolished completely whereas neither LTD nor LTP were affected. These studies provide genetic evidence that the Aalpha isoform of calcineurin is important for the reversal of LTP in the hippocampus and indicate that depotentiation and LTD operate through somewhat different molecular mechanisms.