Exchange protein activated by cyclic AMP 2 (Epac2) plays a specific and time-limited role in memory retrieval

Hippocampus. 2010 Sep;20(9):1018-26. doi: 10.1002/hipo.20700.


Knowledge on the molecular mechanisms involved in memory retrieval is limited due to the lack of tools to study this stage of the memory process. Here we report that exchange proteins activated by cAMP (Epac) play a surprisingly specific role in memory retrieval. Intrahippocampal injection of the Epac activator 8-pCPT-2'O-Me-cAMP was shown to improve fear memory retrieval in contextual fear conditioning whereas acquisition and consolidation were not affected. The retrieval enhancing effect of the Epac activator was even more prominent in the passive avoidance paradigm. Down-regulation of Epac2 expression in the hippocampal CA1 area impaired fear memory retrieval when the memory test was performed 72 h after training, but not when tested after 17 days. Our data thus identify an important time-limited role for hippocampal Epac2 signaling in cognition and opens new avenues to investigate the molecular mechanisms underlying memory retrieval.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / physiology*
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Guanine Nucleotide Exchange Factors / physiology*
  • Hippocampus / chemistry
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Male
  • Memory / drug effects
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Thionucleotides / pharmacology
  • Time Factors


  • Carrier Proteins
  • Guanine Nucleotide Exchange Factors
  • Rapgef4 protein, mouse
  • Thionucleotides
  • 8-((4-chlorophenyl)thio)cyclic-3',5'-AMP
  • Cyclic AMP