The PDE4 Inhibitor HT-0712 Improves Hippocampus-Dependent Memory in Aged Mice

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 39; no. 13; pp. 2938 - 2948
• Main Authors: PETERS, Marco, BLETSCH, Matthew, STANLEY, Jennifer, WHEELER, Damian, SCOTT, Roderick, TULLY, Tim
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.2014
• Subjects: Age; Age Factors; Aging; Aging - drug effects; Animals; Biological and medical sciences; Brain-Derived Neurotrophic Factor - metabolism; Cells, Cultured; Conditioning (Psychology) - drug effects; CREB-Binding Protein - metabolism; Early Growth Response Protein 1 - metabolism; Embryo, Mammalian; Exploratory Behavior - drug effects; Fear - psychology; Gene expression; Gene Expression Regulation - drug effects; Hippocampus - physiology; Male; Maze Learning - drug effects; Medical sciences; Memory; Memory, Long-Term - drug effects; Mice; Neurons - drug effects; Neurons - metabolism; Neurosciences; Original; Phosphodiesterase 4 Inhibitors - pharmacology; Piperidones - pharmacology; Protein Binding - drug effects; Proteins; Proto-Oncogene Proteins c-fos - metabolism; Rolipram - pharmacology; United States > US; Vertebrata; Mammalia; Mouse; Animal; Memory; Rodentia; Central nervous system; Inhibitor; Hippocampus; Encephalon
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2014.154

Aging is associated with declines in memory and cognitive function. Here, we evaluate the effects of HT-0712 on memory formation and on cAMP response element-binding protein (CREB)-regulated genes in aged mice. HT-0712 enhanced long-term memory formation in normal young mice at brain concentrations similar to those found to increase CRE-mediated gene expression in hippocampal neurons. Aged mice showed significantly poorer contextual and trace conditioning compared with young-adult mice. In aged mice, a single injection of HT-0712 significantly boosted contextual and trace long-term memory. Additional effects of HT-0712 were seen in a spatial memory task. Our parallel biochemical experiments revealed that inductions of the CREB-regulated genes, cFos, Zif268, and Bdnf, after fear conditioning were diminished in aged mice. HT-0712 facilitated expression of these CREB-regulated genes in aged hippocampus, indicating that the drug engages a CREB-regulated mechanism in vivo. These findings corroborate and extend our previous results on the mechanism of action of HT-0712 and its efficacy to enhance memory formation. Our data also indicate that HT-0712 may be effective to treat age-associated memory impairment in humans.