Pharmacological inhibition of phosphodiesterase 7 enhances consolidation processes of spatial memory

• Published in: Neurobiology of learning and memory Vol. 177; p. 107357
• Main Authors: McQuown, Susan, Paes, Dean, Baumgärtel, Karsten, Prickaerts, Jos, Peters, Marco
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021
• ISSN: 1074-7427; 1095-9564
• DOI: 10.1016/j.nlm.2020.107357

•Augmentation of cAMP is a therapeutic strategy for improving cognitive function.•Inhibition of PDE4 enhances memory, but less is known about other cAMP specific PDEs.•Selective inhibitors of PDE7 have entered development for diseases of the CNS.•Here, we present evidence for a role of PDE7 in hippocampal memory consolidation.•We show that a selective inhibitor of PDE7 enhances hippocampal memory in rats and mice.•Selectivity and pharmacokinetic profiles of the compound are presented to enable future research.•PDE7 is a novel therapeutic target for memory enhancement. Augmentation of cAMP signaling through inhibition of phosphodiesterases (PDE) is known to enhance plasticity and memory. Inhibition of PDE4 enhances consolidation into memory, but less is known about the role of other cAMP specific PDEs. Here, we tested the effects of oral treatment with a selective inhibitor of PDE7 of nanomolar potency on spatial and contextual memory. In an object location task, doses of 0.3–3 mg/kg administered 3 h after training dose-dependently attenuated time-dependent forgetting in rats. Significant enhancement of memory occurred at a dose of 3 mg/kg with corresponding brain levels consistent with PDE7 inhibition. The same dose given prior to training augmented contextual fear conditioning. In mice, daily dosing before training enhanced spatial memory in two different incremental learning paradigms in the Barnes Maze. Drug treated mice made significantly less errors locating the escape in a probe-test 24 h after the end of training, and they exhibited hippocampal-dependent spatial search strategies more frequently than controls, which tended to show serial sampling of escape locations. Acquisition and short-term memory, in contrast, were unaffected. Our data provide evidence for a role of PDE7 in the consolidation of hippocampal-dependent memory. We suggest that targeting PDE7 for memory enhancement may provide an alternative to PDE4 inhibitors, which tend to have undesirable gastrointestinal side-effects.