Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory

In an attempt to improve behavioral memory, we devised a strategy to amplif y the signal-to-noise ratio of the cAMP pathway, which plays a central role in hippocampal synaptic plasticity and behavioral memory. Multiple high-fr equency trains of electrical stimulation induce long-lasting long-term pote ntiation, a form of synaptic strengthening in hippocampus that is greater i n both magnitude and persistence than the short-lasting long-term potentiat ion generated by a single tetanic train. Studies using pharmacological inhi bitors and genetic manipulations have shown that this difference in respons e depends on the activity of cAMP-dependent protein kinase A. Genetic studi es have also indicated that protein kinase A and one of its target transcri ption factors, cAMP response element binding protein, are important in memo ry in vivo. These findings suggested that amplification of signals through the cAMP pathway might lower the threshold for generating long-lasting long -term potentiation and increase behavioral memory. We therefore examined th e biochemical, physiological, and behavioral effects in mice of partial inh ibition of a hippocampal cAMP phosphodiesterase. Concentrations of a type I V-specific phosphodiesterase inhibitor, rolipram, which had no significant effect on basal cAMP concentration, increased the cAMP response of hippocam pal slices to stimulation with forskolin and induced persistent long-term p otentiation in CA1 after a single tetanic train. In both young and aged mic e, rolipram treatment before training increased long- but not short-term re tention in freezing to context, a hippocampus-dependent memory task.