Learning and memory are complex cognitive functions thought to depend on brain cells plasticity. Numerous studies have suggested that synaptic plasticity and memory rely on protein phosphorylation. Whereas the role of kinases in the brain has largely been demonstrated, the importance of phosphatases remains elusive. We assessed the role that calcineurin (PP2B), a Ca2+/calmodulin-dependent phosphatase, plays in synaptic plasticity, learning and memory with a genetic approach. Transgenic mice expressing an active mutant of calcineurin in forebrain neurons, in a constitutive or regulated manner with the tetracycline-controlled transactivator (tTA) or the reverse tTA (rtTA) systems were generated. In these mice, transgene expression led to an increase in calcineurin activity, that could be suppressed by doxycycline with the tTA system or induced by doxycycline with the rtTA system. Electrophysiological analyses revealed that calcineurin overexpression produced a deficit in a protein kinase A (PKA)-dependent intermediate phase of long-term potentiation (I-LTP) in CA1 Schaffer collateral pathway. The LTP defect could be reversed or induced with respectively, the tTA or the rtTA systems, suggesting a direct effect of the calcineurin transgene [1]. Furthermore, calcineurin-overexpressing mice exhibited impaired spatial and non-spatial hippocampal-dependent memory. Expression of the transgene during various steps of learning revealed a deficit in a transition phase between short-term and long-term memory as well as in the retrieval of spatial memory [2, 3]. Altogether, our results suggest a role for calcineurin in the molecular mechanisms of synaptic plasticity as well as in memory formation, storage and retrieval.