Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory.
Learning-induced synaptic plasticity commonly involves the interaction between cAMP and p42/44MAPK. To investigate the role of Rap1 as a potential signaling molecule coupling cAMP and p42/44MAPK, we expressed an interfering Rap1 mutant (iRap1) in the mouse forebrain. This expression selectively decreased basal phosphorylation of a membrane-associated pool of p42/44MAPK, impaired cAMP-dependent LTP in the hippocampal Schaffer collateral pathway induced by either forskolin or theta frequency stimulation, decreased complex spike firing, and reduced the p42/44MAPK-mediated phosphorylation of the A-type potassium channel Kv4.2. These changes correlated with impaired spatial memory and context discrimination. These results indicate that Rap1 couples cAMP signaling to a selective membrane-associated pool of p42/44MAPK to control excitability of pyramidal cells, the early and late phases of LTP, and the storage of spatial memory.
Morozov
Alexei
A
Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA.
Muzzio
Isabel A
IA
Bourtchouladze
Rusiko
R
Van-Strien
Niels
N
Lapidus
Kyle
K
Yin
DeQi
D
Winder
Danny G
DG
Adams
J Paige
JP
Sweatt
J David
JD
Kandel
Eric R
ER
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D001522:Behavior, Animal; D015153:Blotting, Western; D005576:Colforsin / Q000494:pharmacology; D003213:Conditioning, Psychological; D003463:Cues; D000242:Cyclic AMP / Q000378:metabolism*; D004558:Electric Stimulation; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000033:anatomy & histology / Q000378:metabolism; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D053590:Interleukin 1 Receptor Antagonist Protein; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008568:Memory / Q000502:physiology*; D008667:Metalloproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009154:Mutation; D009473:Neuronal Plasticity / Q000235:genetics* / Q000502:physiology*; D016548:Prosencephalon / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time; D012795:Sialoglycoproteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D013742:Tetanus; D013826:Theta Rhythm; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C446049:AcsF protein, Rubrivivax gelatinosus; D018501:Antirheumatic Agents; D001426:Bacterial Proteins; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D008667:Metalloproteins; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D005576:Colforsin; C056639:2-amino-5-phosphopentanoic acid; D000242:Cyclic AMP; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins; D014633:Valine