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.
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. cisiegas@sas.upenn.edu
Carolina
C
Isiegas
Conor
C
McDonough
Ted
T
Huang
Robbert
R
Havekes
Sara
S
Fabian
Long-Jun
LJ
Wu
Hui
H
Xu
Ming-Gao
MG
Zhao
Jae-Ick
JI
Kim
Yong-Seok
YS
Lee
Hye-Ryeon
HR
Lee
Hyoung-Gon
HG
Ko
Nuribalhae
N
Lee
Sun-Lim
SL
Choi
Jeong-Sik
JS
Lee
Hyeon
H
Son
Min
M
Zhuo
Bong-Kiun
BK
Kaang
Ted
T
Abel
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