A novel conditional genetic system reveals that increasing neuronal cAMP enhances memory and retrieval.
Consistent evidence from pharmacological and genetic studies shows that cAMP is a critical modulator of synaptic plasticity and memory formation. However, the potential of the cAMP signaling pathway as a target for memory enhancement remains unclear because of contradictory findings from pharmacological and genetic approaches. To address these issues, we have developed a novel conditional genetic system in mice based on the heterologous expression of an Aplysia octopamine receptor, a G-protein-coupled receptor whose activation by its natural ligand octopamine leads to rapid and transient increases in cAMP. We find that activation of this receptor transgenically expressed in mouse forebrain neurons induces a rapid elevation of hippocampal cAMP levels, facilitates hippocampus synaptic plasticity, and enhances the consolidation and retrieval of fear memory. Our findings clearly demonstrate that acute increases in cAMP levels selectively in neurons facilitate synaptic plasticity and memory, and illustrate the potential of this heterologous system to study cAMP-mediated processes in mammalian systems.
Isiegas
Carolina
C
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. cisiegas@sas.upenn.edu
McDonough
Conor
C
Huang
Ted
T
Havekes
Robbert
R
Fabian
Sara
S
Wu
Long-Jun
LJ
Xu
Hui
H
Zhao
Ming-Gao
MG
Kim
Jae-Ick
JI
Lee
Yong-Seok
YS
Lee
Hye-Ryeon
HR
Ko
Hyoung-Gon
HG
Lee
Nuribalhae
N
Choi
Sun-Lim
SL
Lee
Jeong-Sik
JS
Son
Hyeon
H
Zhuo
Min
M
Kaang
Bong-Kiun
BK
Abel
Ted
T
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009655:Octopamine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010364:Pattern Recognition, Visual / Q000187:drug effects / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017982:Receptors, Biogenic Amine / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects
D000316:Adrenergic alpha-Agonists; D017362:Cyclic AMP Response Element-Binding Protein; D017982:Receptors, Biogenic Amine; C027604:norsynephrine receptor; D009655:Octopamine; D000242:Cyclic AMP; D010751:Phosphopyruvate Hydratase