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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 RIS Download

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

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM08042
  • Agency: NIMH NIH HHS, Id: MH063541
  • Agency: NIGMS NIH HHS, Id: T32 GM008042
  • Agency: NINDS NIH HHS, Id: R01 NS040593
  • Agency: NIMH NIH HHS, Id: F30 MH063541
  • Agency: NINDS NIH HHS, Id: R01 NS040593-09
  • Agency: NINDS NIH HHS, Id: R01 NS038480

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