Translational control by MAPK signaling in long-term synaptic plasticity and memory

Cell. 2004 Feb 6;116(3):467-79. doi: 10.1016/s0092-8674(04)00115-1.

Abstract

Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. Here, we investigate the role of MAPK signaling in these processes. Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation-dependent, transcription-independent phase of hippocampal L-LTP. In hippocampal neurons, ERK inhibition blocked neuronal activity-induced translation as well as phosphorylation of the translation factors eIF4E, 4EBP1, and ribosomal protein S6. Correspondingly, protein synthesis and translation factor phosphorylation induced in control hippocampal slices by L-LTP-generating tetanization were significantly reduced in mutant slices. Translation factor phosphorylation induced in the control hippocampus by memory formation was similarly diminished in the mutant hippocampus. These results suggest a crucial role for translational control by MAPK signaling in long-lasting forms of synaptic plasticity and memory.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factors
  • Gene Expression Regulation, Enzymologic / genetics
  • Hippocampus / cytology
  • Hippocampus / enzymology
  • Hippocampus / growth & development
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • MAP Kinase Kinase 1
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Memory / drug effects
  • Memory / physiology*
  • Memory Disorders / enzymology
  • Memory Disorders / genetics
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation / genetics
  • Neuronal Plasticity / physiology*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Biosynthesis / physiology*
  • Rats
  • Ribosomal Protein S6 / genetics
  • Ribosomal Protein S6 / metabolism
  • Synapses / drug effects
  • Synapses / enzymology*
  • Synapses / ultrastructure

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eif4ebp1 protein, rat
  • Enzyme Inhibitors
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Ribosomal Protein S6
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases