QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 19, 2005, 25(42):9721-9734; doi:10.1523/JNEUROSCI.2836-05.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Kushner, S. A. Articles by Silva, A. J. Search for Related Content PubMed PubMed Citation Articles by Kushner, S. A. Articles by Silva, A. J.

 Previous Article  |  Next Article 

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 and Alcino 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-ras^G12V), 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.

This article has been cited by other articles:

				J. A. Dickinson, J. N. C. Kew, and S. Wonnacott Presynaptic {alpha}7- and {beta}2-Containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release from Rat Prefrontal Cortex Nerve Terminals via Distinct Cellular Mechanisms Mol. Pharmacol., August 1, 2008; 74(2): 348 - 359. [Abstract] [Full Text] [PDF]

				D. Jaarsma, E. Teuling, E. D. Haasdijk, C. I. De Zeeuw, and C. C. Hoogenraad Neuron-Specific Expression of Mutant Superoxide Dismutase Is Sufficient to Induce Amyotrophic Lateral Sclerosis in Transgenic Mice J. Neurosci., February 27, 2008; 28(9): 2075 - 2088. [Abstract] [Full Text] [PDF]

				D. Fioravante, R.-Y. Liu, A. K. Netek, L. J. Cleary, and J. H. Byrne Synapsin Regulates Basal Synaptic Strength, Synaptic Depression, and Serotonin-Induced Facilitation of Sensorimotor Synapses in Aplysia J Neurophysiol, December 1, 2007; 98(6): 3568 - 3580. [Abstract] [Full Text] [PDF]

				F. Fiumara, C. Milanese, A. Corradi, S. Giovedi, G. Leitinger, A. Menegon, P. G. Montarolo, F. Benfenati, and M. Ghirardi Phosphorylation of synapsin domain A is required for post-tetanic potentiation J. Cell Sci., September 15, 2007; 120(18): 3228 - 3237. [Abstract] [Full Text] [PDF]

				M. Sun, M. J. Thomas, R. Herder, M. L. Bofenkamp, S. B. Selleck, and M. B. O'Connor Presynaptic Contributions of Chordin to Hippocampal Plasticity and Spatial Learning J. Neurosci., July 18, 2007; 27(29): 7740 - 7750. [Abstract] [Full Text] [PDF]

				B. J. Wiltgen and A. J. Silva Memory for context becomes less specific with time Learn. Mem., April 10, 2007; 14(4): 313 - 317. [Abstract] [Full Text] [PDF]

				R. F. G. Toonen, K. Wierda, M. S. Sons, H. de Wit, L. N. Cornelisse, A. Brussaard, J. J. Plomp, and M. Verhage Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size PNAS, November 28, 2006; 103(48): 18332 - 18337. [Abstract] [Full Text] [PDF]

				R. Tonini, S. Ciardo, M. Cerovic, T. Rubino, D. Parolaro, M. Mazzanti, and R. Zippel ERK-Dependent Modulation of Cerebellar Synaptic Plasticity after Chronic {Delta}9-Tetrahydrocannabinol Exposure J. Neurosci., May 24, 2006; 26(21): 5810 - 5818. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help