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.

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