Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling

J Neurosci. 2011 Jan 5;31(1):172-83. doi: 10.1523/JNEUROSCI.5236-10.2011.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Bromodeoxyuridine / metabolism
  • CREB-Binding Protein / metabolism
  • Cyclic AMP / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / deficiency*
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Green Fluorescent Proteins / genetics
  • Hippocampus / cytology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory / drug effects
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Knockout
  • MicroRNAs / pharmacology
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Neurogenesis / physiology*
  • Neuropsychological Tests
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • RNA Interference / physiology*
  • Recognition, Psychology / drug effects
  • Recognition, Psychology / physiology
  • Rolipram / pharmacology
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Time Factors


  • MicroRNAs
  • Nerve Tissue Proteins
  • Phosphodiesterase 4 Inhibitors
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Cyclic AMP
  • CREB-Binding Protein
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, mouse
  • Bromodeoxyuridine
  • Rolipram