PT  - JOURNAL ARTICLE
AU  - Steven A. Kushner
AU  - Ype Elgersma
AU  - Geoffrey G. Murphy
AU  - Dick Jaarsma
AU  - Geeske M. van Woerden
AU  - Mohammad Reza Hojjati
AU  - Yijun Cui
AU  - Janelle C. LeBoutillier
AU  - Diano F. Marrone
AU  - Esther S. Choi
AU  - Chris I. De Zeeuw
AU  - Ted L. Petit
AU  - Lucas Pozzo-Miller
AU  - Alcino J. Silva
TI  - Modulation of Presynaptic Plasticity and Learning by the H-ras/Extracellular Signal-Regulated Kinase/Synapsin I Signaling Pathway
AID  - 10.1523/JNEUROSCI.2836-05.2005
DP  - 2005 Oct 19
TA  - The Journal of Neuroscience
PG  - 9721--9734
VI  - 25
IP  - 42
4099  - http://www.jneurosci.org/content/25/42/9721.short
4100  - http://www.jneurosci.org/content/25/42/9721.full
SO  - J. Neurosci.2005 Oct 19; 25
AB  - 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.