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The Journal of Neuroscience, October 19, 2005, 25(42):9721-9734; doi:10.1523/JNEUROSCI.2836-05.2005
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Cellular/Molecular
Modulation of Presynaptic Plasticity and Learning by the H-ras/Extracellular Signal-Regulated Kinase/Synapsin I Signaling Pathway
Steven A. Kushner,1 * Ype Elgersma,1,2 * Geoffrey G. Murphy,1 Dick Jaarsma,2 Geeske M. van Woerden,2 Mohammad Reza Hojjati,2 Yijun Cui,1 Janelle C. LeBoutillier,3 Diano F. Marrone,3 Esther S. Choi,1 Chris I. De Zeeuw,2 Ted L. Petit,3 Lucas Pozzo-Miller,4 andAlcino J. Silva1 1Departments of Neurobiology, Psychiatry, and Psychology, Brain Research Institute, University of California, Los Angeles, California 90095-1761, 2Department of Neuroscience, Erasmus Medical Center Rotterdam, 3000 DR Rotterdam, The Netherlands, 3Department of Psychology and Program in Neuroscience, University of Toronto, Scarborough, Ontario, Canada M1C 1A4, and 4Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0021
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.
Key words: Ras; ERK; synapsin; LTP; miniature excitatory postsynaptic currents; mEPSCs; learning; resynaptic
Received July 10, 2005; revised September 1, 2005; accepted September 7, 2005.
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