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PNAS 99 (1): 467-472

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROBIOLOGY

A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus

Shao Jun Tang*, Gerald Reis*, Hyejin Kang*, Anne-Claude Gingras{dagger}, Nahum Sonenberg{dagger}, and Erin M. Schuman*,{ddagger}

*California Institute of Technology, Howard Hughes Medical Institute, Division of Biology 216-76, Pasadena, CA 91125; and {dagger}Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6

Accepted for publication November 12, 2001.

Received for publication September 17, 2001.

Abstract: Many forms of long-lasting behavioral and synaptic plasticity require the synthesis of new proteins. For example, long-term potentiation (LTP) that endures for more than an hour requires both transcription and translation. The signal-transduction mechanisms that couple synaptic events to protein translational machinery during long-lasting synaptic plasticity, however, are not well understood. One signaling pathway that is stimulated by growth factors and results in the translation of specific mRNAs includes the rapamycin-sensitive kinase mammalian target of rapamycin (mTOR, also known as FRAP and RAFT-1). Several components of this translational signaling pathway, including mTOR, eukaryotic initiation factor-4E-binding proteins 1 and 2, and eukaryotic initiation factor-4E, are present in the rat hippocampus as shown by Western blot analysis, and these proteins are detected in the cell bodies and dendrites in the hippocampal slices by immunostaining studies. In cultured hippocampal neurons, these proteins are present in dendrites and are often found near the presynaptic protein, synapsin I. At synaptic sites, their distribution completely overlaps with a postsynaptic protein, PSD-95. These observations suggest the postsynaptic localization of these proteins. Disruption of mTOR signaling by rapamycin results in a reduction of late-phase LTP expression induced by high-frequency stimulation; the early phase of LTP is unaffected. Rapamycin also blocks the synaptic potentiation induced by brain-derived neurotrophic factor in hippocampal slices. These results demonstrate an essential role for rapamycin-sensitive signaling in the expression of two forms of synaptic plasticity that require new protein synthesis. The localization of this translational signaling pathway at postsynaptic sites may provide a mechanism that controls local protein synthesis at potentiated synapses.

{ddagger} To whom reprint requests should be addressed. E-mail: schumane{at}cco.caltech.edu.

Communicated by Norman Davidson, California Institute of Technology, Pasadena, CA

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BDNF induces translocation of initiation factor 4E to mRNA granules: Evidence for a role of synaptic microfilaments and integrins.
F. M. Smart, G. M. Edelman, and P. W. Vanderklish (2003)
PNAS 100, 14403-14408
   Abstract »    Full Text »    PDF »
Axonal transport of eukaryotic translation elongation factor 1{alpha} mRNA couples transcription in the nucleus to long-term facilitation at the synapse.
M. Giustetto, A. N. Hegde, K. Si, A. Casadio, K. Inokuchi, W. Pei, E. R. Kandel, and J. H. Schwartz (2003)
PNAS 100, 13680-13685
   Abstract »    Full Text »    PDF »
mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo.
C.-H. Kwon, X. Zhu, J. Zhang, and S. J. Baker (2003)
PNAS 100, 12923-12928
   Abstract »    Full Text »    PDF »
Two previously undescribed members of the mouse CPEB family of genes and their inducible expression in the principal cell layers of the hippocampus.
M. Theis, K. Si, and E. R. Kandel (2003)
PNAS 100, 9602-9607
   Abstract »    Full Text »    PDF »
Estrogen Stimulates Postsynaptic Density-95 Rapid Protein Synthesis via the Akt/Protein Kinase B Pathway.
K. T. Akama and B. S. McEwen (2003)
J. Neurosci. 23, 2333-2339
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Estrogen Levels Regulate the Subcellular Distribution of Phosphorylated Akt in Hippocampal CA1 Dendrites.
V. Znamensky, K. T. Akama, B. S. McEwen, and T. A. Milner (2003)
J. Neurosci. 23, 2340-2347
   Abstract »    Full Text »    PDF »
Protein Synthesis Is Required for Synaptic Immunity to Depotentiation.
N. H. Woo and P. V. Nguyen (2003)
J. Neurosci. 23, 1125-1132
   Abstract »    Full Text »    PDF »
Dendritic BC1 RNA: Functional Role in Regulation of Translation Initiation.
H. Wang, A. Iacoangeli, S. Popp, I. A. Muslimov, H. Imataka, N. Sonenberg, I. B. Lomakin, and H. Tiedge (2002)
J. Neurosci. 22, 10232-10241
   Abstract »    Full Text »    PDF »
The Group I Metabotropic Glutamate Receptor Agonist (S)-3,5-Dihydroxyphenylglycine Induces a Novel Form of Depotentiation in the CA1 Region of the Hippocampus.
W.-M. Zho, J.-L. You, C.-C. Huang, and K.-S. Hsu (2002)
J. Neurosci. 22, 8838-8849
   Abstract »    Full Text »    PDF »
Brain-Derived Neurotrophic Factor Triggers Transcription-Dependent, Late Phase Long-Term Potentiation In Vivo.
E. Messaoudi, S.-W. Ying, T. Kanhema, S. D. Croll, and C. R. Bramham (2002)
J. Neurosci. 22, 7453-7461
   Abstract »    Full Text »    PDF »
Nerve Growth Factor Specifically Stimulates Translation of Eukaryotic Elongation Factor 1A-1 (eEF1A-1) mRNA by Recruitment to Polyribosomes in PC12 Cells.
E. Petroulakis and E. Wang (2002)
J. Biol. Chem. 277, 18718-18727
   Abstract »    Full Text »    PDF »

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