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.
Kushner
Steven A
SA
Department of Neurobiology, Brain Research Institute, University of California, Los Angeles, California 90095-1761, USA.
Elgersma
Ype
Y
Murphy
Geoffrey G
GG
Jaarsma
Dick
D
van Woerden
Geeske M
GM
Hojjati
Mohammad Reza
MR
Cui
Yijun
Y
LeBoutillier
Janelle C
JC
Marrone
Diano F
DF
Choi
Esther S
ES
De Zeeuw
Chris I
CI
Petit
Ted L
TL
Pozzo-Miller
Lucas
L
Silva
Alcino J
AJ
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
D016704:Synapsins; D048049:Extracellular Signal-Regulated MAP Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)