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

Abstract

In an attempt to improve behavioral memory, we devised a strategy to amplify the signal-to-noise ratio of the cAMP pathway, which plays a central role in hippocampal synaptic plasticity and behavioral memory. Multiple highfrequency trains of electrical stimulation induce long-lasting long-term potentiation, a form of synaptic strengthening in hippocampus that is greater in both magnitude and persistence than the short-lasting long-term potentiation generated by a single tetanic train. Studies using pharmacological inhibitors and genetic manipulations have shown that this difference in response depends on the activity of cAMPdependent protein kinase A. Genetic studies have also indicated that protein kinase A and one of its target transcription factors, cAMP response element binding protein, are important in memory 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 the biochemical, physiological, and behavioral effects in mice of partial inhibition of a hippocampal cAMP phosphodiesterase. Concentrations of a type IV-specific phosphodiesterase inhibitor, rolipram, which had no significant effect on basal cAMP concentration, increased the cAMP response of hippocampal slices to stimulation with forskolin and induced persistent long-term potentiation in CA1 after a single tetanic train. In both young and aged mice, rolipram treatment before training increased long-but not short-term retention in freezing to context, a hippocampus-dependent memory task.The second messenger, cAMP, and cAMP-dependent protein kinase A (PKA) have been implicated in short-and longlasting synaptic plasticity in Aplysia and in short-and longlasting behavioral learning in Aplysia and Drosophila (1, 2). Recently, convergent pharmacological and genetic evidence has also implicated the cAMP system in short-lasting longterm potentiation (LTP) at the mossy fiber-CA3 synapse of rodent hippocampus (3-6), and, strikingly, in the stronger longer-lasting intermediate and late phases of long-lasting LTP (L-LTP) that follow three to four trains of tetanic stimulation in all three hippocampal pathways: the perforant, the mossy fiber, and the Schaeffer collateral (CA3-CA1) (3,(7)(8)(9)(10)(11)(12)(13)(14). LTP is a well studied example of synaptic plasticity in mammals, thought to be a candidate cellular mechanism for mediating some forms of explicit hippocampus-dependent memory (15, 16). L-LTP has been of particular interest in regard to this behavioral correlation, because it is much more persistent than the short-lasting long-term potentiation that follows a single tetanic train (7,8,9). L-LTP persists as long as it has been observed, up to 29 hr in vitro, and depends at later time points not only on PKA activity but also on transcription and translation (3,6,8,9), much like behavioral long-term memory.The dependence of L-LTP, in hippocampal slices and behavioral memory, on PKA a...

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…While overall inhibition of PDE4 enhances memory performance in animals (Barad et al, 1998;Zhang et al, 2004Zhang et al, , 2005, PDE4BÀ/À mice did not show significant changes in either short-or long-term memory in step-down passive avoidance and Morris water-maze tasks (Table 1 and Figure 5), two tests measuring hippocampus-based memory (Bevilaqua et al, 1997). This is consistent with the limited expression of PDE4B in the hippocampus (Cherry and Davis, 1999).…”

“…It is well established that PDE4 inhibitors such as rolipram produce antidepressant-like and memory-enhancing effects (Barad et al, 1998;O'Donnell and Zhang, 2004;Zhang et al, 2004Zhang et al, , 2006Zhang and O'Donnell, 2007). They also may induce anxiogenic-like effects and sedation (Heaslip and Evans, 1995;Imaizumi et al, 1994;Silvestre et al, 1999b), although an anxiolytic-like effect also has been reported (Silvestre et al, 1999a).…”

“…Phosphodiesterase-4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cyclic AMP (cAMP) and is critical in controlling its intracellular concentration, is involved in various central nervous system (CNS) processes, including depression , learning and memory (Barad et al, 1998), anxiety (Beer et al, 1972), and analgesia (Bradaia et al, 2005). Administration of PDE4 inhibitors such as rolipram produces antidepressant-like effects (Zhang et al, 2002(Zhang et al, , 2006, reverses memory deficits induced pharmacologically, physically, or genetically (Bourtchouladze et al, 2003;Imanishi et al, 1997;Zhang et al, 2000Zhang et al, , 2004, alters anxiogenic-like behavior (Imaizumi et al, 1994;Silvestre et al, 1999a), and induces analgesia in rodents (Kumar et al, 2000).…”

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

“…Rolipram also enhances memory (Barad et al, 1998;Bourtchouladze et al, 2003;Zhang et al, 2004). This, coupled with the effect of rolipram on PPI, suggests that cAMP PDE inhibitors may prove successful in treating the debilitating cognitive deficits that are associated with schizophrenia.…”

Modulation of the cAMP signaling pathway after traumatic brain injury

“…In the uninjured CNS, rolipram increases cAMP levels in the hippocampus (Barad et al, 1998, Van Staveren et al, 2001, Giorgi et al, 2004, and specifically in microglia and astrocytes as compared to neurons (Zhang et al, 2002). There are also very modest increases in cGMP levels with high concentrations of rolipram, suggesting that rolipram could work through cGMP although this is more unlikely (Van Staveren et al, 2001).…”