Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade

Brain Res Mol Brain Res. 2000 Mar 10;76(1):36-46. doi: 10.1016/s0169-328x(99)00329-0.


It is widely accepted that the formation of long-term memory (LTM) requires neuronal gene expression, protein synthesis and the remodeling of synaptic contacts. From mollusk to mammals, the cAMP/PKA/CREB signaling pathway has been shown to play a pivotal role in the establishment of LTM. More recently, the MAPK cascade has been also involved in memory processing. Here, we provide evidence for the participation of hippocampal PKA/CREB and MAPK/Elk-1 pathways, via activation of NMDA receptors, in memory formation of a one-trial avoidance learning in rats. Learning of this task is associated with an activation of p44 and p42 MAPKs, CREB and Elk-1, along with an increase in the levels of the catalytic subunit of PKA and Fos protein in nuclear-enriched hippocampal fractions. These changes were blocked by the immediate posttraining intra-hippocampal infusion of APV, a selective blocker of glutamate NMDA receptors, which renders the animals amnesic for this task. Moreover, no changes were found in control-shocked animals. Thus, inhibitory avoidance training in the rat is associated with an increase in the protein product of an IEG, c-fos, which occurs concomitantly with the activation of nuclear MAPK, CREB and Elk-1. NMDA receptors appear to be a necessary upstream step for the activation of these intracellular cascades during learning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Avoidance Learning*
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • DNA-Binding Proteins*
  • Electrophoresis, Polyacrylamide Gel
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hippocampus / metabolism*
  • Immunoblotting
  • Male
  • Microinjections
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / biosynthesis*
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Transcription Factors / metabolism*
  • ets-Domain Protein Elk-1


  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Elk1 protein, rat
  • Excitatory Amino Acid Antagonists
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Receptors, N-Methyl-D-Aspartate
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • 2-Amino-5-phosphonovalerate
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases