A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus.
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.
Tang
Shao Jun
SJ
California Institute of Technology, Howard Hughes Medical Institute, Division of Biology 216-76, Pasadena, CA 91125, USA.
Reis
Gerald
G
Kang
Hyejin
H
Gingras
Anne-Claude
AC
Sonenberg
Nahum
N
Schuman
Erin M
EM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins; D000076122:Disks Large Homolog 4 Protein; D004594:Electrophysiology; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D005260:Female; D051528:Guanylate Kinases; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology*; D007074:Immunoglobulin G / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D011485:Protein Binding; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism* / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; C499527:Eif4ebp1 protein, mouse; C499526:Eif4ebp1 protein, rat; C491255:Eif4ebp2 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; C033652:postsynaptic density proteins; D011494:Protein Kinases; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D051528:Guanylate Kinases; D020123:Sirolimus