Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory

Alexei Morozov; Isabel A Muzzio; Rusiko Bourtchouladze; Niels Van-Strien; Kyle Lapidus; DeQi Yin; Danny G Winder; J Paige Adams; J David Sweatt; Eric R Kandel

doi:10.1016/s0896-6273(03)00404-5

Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory

Neuron. 2003 Jul 17;39(2):309-25. doi: 10.1016/s0896-6273(03)00404-5.

Authors

Alexei Morozov¹, Isabel A Muzzio, Rusiko Bourtchouladze, Niels Van-Strien, Kyle Lapidus, DeQi Yin, Danny G Winder, J Paige Adams, J David Sweatt, Eric R Kandel

Affiliation

¹ Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA.

PMID: 12873387
DOI: 10.1016/s0896-6273(03)00404-5

Abstract

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antirheumatic Agents / pharmacology
Bacterial Proteins*
Behavior, Animal
Blotting, Western
Colforsin / pharmacology
Conditioning, Psychological
Cues
Cyclic AMP / metabolism*
Electric Stimulation
Electrophysiology
Excitatory Postsynaptic Potentials
Gene Expression Regulation, Enzymologic
Hippocampus / anatomy & histology
Hippocampus / metabolism
Immunoenzyme Techniques
In Situ Hybridization
Interleukin 1 Receptor Antagonist Protein
Long-Term Potentiation / genetics
Long-Term Potentiation / physiology
Memory / physiology*
Metalloproteins / metabolism
Mice
Mice, Transgenic
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / physiology*
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases / physiology*
Mutation
Neuronal Plasticity / genetics*
Neuronal Plasticity / physiology*
Prosencephalon / metabolism
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf / metabolism
RNA, Messenger / biosynthesis
Reaction Time
Sialoglycoproteins / pharmacology
Signal Transduction / physiology
Subcellular Fractions / metabolism
Synapses / metabolism*
Synaptic Transmission / genetics
Synaptic Transmission / physiology
Tetanus
Theta Rhythm
Valine / analogs & derivatives*
Valine / pharmacology
rap1 GTP-Binding Proteins / genetics
rap1 GTP-Binding Proteins / metabolism*

Substances

AcsF protein, Rubrivivax gelatinosus
Antirheumatic Agents
Bacterial Proteins
Il1rn protein, mouse
Interleukin 1 Receptor Antagonist Protein
Metalloproteins
RNA, Messenger
Sialoglycoproteins
Colforsin
2-amino-5-phosphopentanoic acid
Cyclic AMP
Braf protein, mouse
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
rap1 GTP-Binding Proteins
Valine