Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus.
cAMP is a critical second messenger implicated in synaptic plasticity and memory in the mammalian brain. Substantial evidence links increases in intracellular cAMP to activation of cAMP-dependent protein kinase (PKA) and subsequent phosphorylation of downstream effectors (transcription factors, receptors, protein kinases) necessary for long-term potentiation (LTP) of synaptic strength. However, cAMP may also initiate signaling via a guanine nucleotide exchange protein directly activated by cAMP (Epac). The role of Epac in hippocampal synaptic plasticity is unknown. We found that in area CA1 of mouse hippocampal slices, activation of Epac enhances maintenance of LTP without affecting basal synaptic transmission. The persistence of this form of LTP requires extracellular signal-regulated protein kinase (ERK) and new protein synthesis, but not transcription. Because ERK is involved in translational control of long-lasting plasticity and memory, our data suggest that Epac is a crucial link between cAMP and ERK during some forms of protein synthesis-dependent LTP. Activation of Epac represents a novel signaling pathway for rapid regulation of the stability of enduring forms of LTP and, perhaps, of hippocampus- dependent long-term memories.
Department of Physiology, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada.
Jennifer N
JN
Gelinas
Jessica L
JL
Banko
Melinda M
MM
Peters
Eric
E
Klann
Edwin J
EJ
Weeber
Peter V
PV
Nguyen
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D003609:Dactinomycin / Q000494:pharmacology; D004640:Emetine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D002070:Butadienes; D002227:Carbazoles; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C113580:U 0126; D003609:Dactinomycin; C057416:KT 5720; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol; D004640:Emetine