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Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway.

Molecular and cellular studies of the mechanisms underlying mammalian learning and memory have focused almost exclusively on postsynaptic function. We now reveal an experience-dependent presynaptic mechanism that modulates learning and synaptic plasticity in mice. Consistent with a presynaptic function for endogenous H-ras/extracellular signal-regulated kinase (ERK) signaling, we observed that, under normal physiologic conditions in wild-type mice, hippocampus-dependent learning stimulated the ERK-dependent phosphorylation of synapsin I, and MEK (MAP kinase kinase)/ERK inhibition selectively decreased the frequency of miniature EPSCs. By generating transgenic mice expressing a constitutively active form of H-ras (H-rasG12V), which is abundantly localized in axon terminals, we were able to increase the ERK-dependent phosphorylation of synapsin I. This resulted in several presynaptic changes, including a higher density of docked neurotransmitter vesicles in glutamatergic terminals, an increased frequency of miniature EPSCs, and increased paired-pulse facilitation. In addition, we observed facilitated neurotransmitter release selectively during high-frequency activity with consequent increases in long-term potentiation. Moreover, these mice showed dramatic enhancements in hippocampus-dependent learning. Importantly, deletion of synapsin I, an exclusively presynaptic protein, blocked the enhancements of learning, presynaptic plasticity, and long-term potentiation. Together with previous invertebrate studies, these results demonstrate that presynaptic plasticity represents an important evolutionarily conserved mechanism for modulating learning and memory.

Pubmed ID: 16237176


  • Kushner SA
  • Elgersma Y
  • Murphy GG
  • Jaarsma D
  • van Woerden GM
  • Hojjati MR
  • Cui Y
  • LeBoutillier JC
  • Marrone DF
  • Choi ES
  • De Zeeuw CI
  • Petit TL
  • Pozzo-Miller L
  • Silva AJ


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

October 19, 2005

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM08042
  • Agency: NIMH NIH HHS, Id: MH063541
  • Agency: NINDS NIH HHS, Id: R01 NS038480
  • Agency: NINDS NIH HHS, Id: R01 NS040593
  • Agency: NINDS NIH HHS, Id: R01 NS040593-09

Mesh Terms

  • Animals
  • Extracellular Signal-Regulated MAP Kinases
  • Humans
  • Learning
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neuronal Plasticity
  • Presynaptic Terminals
  • Proto-Oncogene Proteins p21(ras)
  • Synapsins