title: Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway.
abstract: 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.
authors.affiliation: Department of Neurobiology, Brain Research Institute, University of California, Los Angeles, California 90095-1761, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kushner
authors.forename: Ype
authors.initials: Y
authors.lastname: Elgersma
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Murphy
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
authors.forename: Geeske M
authors.initials: GM
authors.lastname: van Woerden
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Hojjati
authors.forename: Yijun
authors.initials: Y
authors.lastname: Cui
authors.forename: Janelle C
authors.initials: JC
authors.lastname: LeBoutillier
authors.forename: Diano F
authors.initials: DF
authors.lastname: Marrone
authors.forename: Esther S
authors.initials: ES
authors.lastname: Choi
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.forename: Ted L
authors.initials: TL
authors.lastname: Petit
authors.forename: Lucas
authors.initials: L
authors.lastname: Pozzo-Miller
authors.forename: Alcino J
authors.initials: AJ
authors.lastname: Silva
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007858:Learning / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D017729:Presynaptic Terminals / Q000201:enzymology; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016704:Synapsins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016704:Synapsins; D048049:Extracellular Signal-Regulated MAP Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)