ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2011
Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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Who cites it
111 citing papers in PubMed, 232 citations in OpenAlex.
- Sub-Chronic Consumption of Dark Chocolate Enhances Cognitive Function and Releases Nerve Growth Factors: A Parallel-Group Randomized Trial.Nutrients · 2019Trial
- Splice isoforms of the histone variant macroH2A1 differentially regulate hippocampal gene expression and memory formation.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- [ModifiedNan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- The Emerging Role of Phosphodiesterase Inhibitors in Fragile X Syndrome and Autism Spectrum Disorder.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Differential effects of Phosphodiesterase 4A5 on cAMP-dependent forms of long-term potentiation.The Journal of physiology · 2025Article
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Inhibition of Phosphodiesterase 4 Suppresses Neuronal Ferroptosis After Cerebral Ischemia/Reperfusion.Molecular neurobiology · 2025Article
- Review
- Genetics and Molecular Biology of Memory Suppression.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2024Review
- Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.Psychopharmacology · 2024Article
- Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?Brain communications · 2024Review
- Phosphodiesterase 4 inhibition after retrieval switches the memory fate favoring extinction instead of reconsolidation.Scientific reports · 2023Article
- Phosphodiesterase and psychiatric disorders: a two-sample Mendelian randomization study.Journal of translational medicine · 2023Article
- Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-β pathology.Cellular and molecular life sciences : CMLS · 2023Article
- Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling.Cell reports · 2023Article
- Phosphodiesterase 4B inhibition: a potential novel strategy for treating pulmonary fibrosis.European respiratory review : an official journal of the European Respiratory Society · 2023Review
- Inhibition of phosphodiesterase-4 in the spinal dorsal horn ameliorates neuropathic pain via cAMP-cytokine-Cx43 signaling in mice.CNS neuroscience & therapeutics · 2022Article
- Potential mechanisms underlying the therapeutic roles of sinisan formula in depression: Based on network pharmacology and molecular docking study.Frontiers in psychiatry · 2022Article
- Article
- CTRP4 ablation impairs associative learning and memory.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
51 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Phosphodiesterase-4 (PDE4) plays an important role in mediating memory via the control of intracellular cAMP signaling; inhibition of PDE4 enhances memory. However, development of PDE4 inhibitors as memory enhancers has been hampered by their major side effect of emesis. PDE4 has four subtypes (PDE4A-D) consisting of 25 splice variants. Mice deficient in PDE4D displayed memory enhancement in radial arm maze, water maze, and object recognition tests. These effects were mimicked by repeated treatment with rolipram in wild-type mice. In addition, similarly as rolipram-treated wild-type mice, PDE4D-deficient mice also displayed increased hippocampal neurogenesis and phosphorylated cAMP response element-binding protein (pCREB). Furthermore, microinfusion of lentiviral vectors that contained microRNAs (miRNAs) targeting long-form PDE4D isoforms into bilateral dentate gyri of the mouse hippocampus downregulated PDE4D4 and PDE4D5, enhanced memory, and increased hippocampal neurogenesis and pCREB. Finally, while rolipram and PDE4D deficiency shortened α2 adrenergic receptor-mediated anesthesia, a surrogate measure of emesis, miRNA-mediated PDE4D knock-down in the hippocampus did not. The present results suggest that PDE4D, in particular long-form PDE4D, plays a critical role in the mediation of memory and hippocampal neurogenesis, which are mediated by cAMP/CREB signaling; reduced expression of PDE4D, or at least PDE4D4 and PDE4D5, in the hippocampus enhances memory but appears not to cause emesis. These novel findings will aid in the development of PDE4 subtype- or variant-selective inhibitors for treatment of disorders involving impaired cognition, including Alzheimer's disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.