PMID- 14623952 OWN - NLM STAT- MEDLINE DCOM- 20040202 LR - 20211203 IS - 0027-8424 (Print) IS - 1091-6490 (Electronic) IS - 0027-8424 (Linking) VI - 100 IP - 24 DP - 2003 Nov 25 TI - Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. PG - 14368-73 AB - Mammalian target of rapamycin (mTOR) is a key regulator of translational capacity. The mTOR inhibitor rapamycin can prevent forms of protein synthesis-dependent synaptic plasticity such as long-term facilitation in Aplysia and late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of rodents. In the latter model, two issues remain to be addressed: defining the L-LTP phase sensitive to rapamycin and identifying the site of rapamycin-sensitive protein synthesis. Here, we show that L-LTP is sensitive to application of rapamycin only during the induction paradigm, whereas rapamycin application after the establishment of L-LTP was ineffective. Second, we observed that Thr-389-phosphorylated p70 S6 kinase (p70S6K), the main active phosphoform of the mTOR effector p70S6K, was induced in an N-methyl-D-aspartate and phosphatidylinositol 3-kinase-dependent manner throughout the dendrites but not in the cell bodies of CA1 neurons in hippocampal slices after L-LTP induction. A similar dendrite-wide activation of p70S6K was induced in primary hippocampal neurons by depolarization with KCL or glutamate. In primary hippocampal neurons, the sites of dendritic activation of p70S6K appeared as discrete compartments along dendritic shafts like the hotspots for fast dendritic translation. Conversely, only a subset of dendritic spines also displayed activated p70S6K. Taken together, the present data suggest that the N-methyl-d-aspartate-, phosphatidylinositol 3-kinase-dependent dendritic activation of the mTOR-p70S6K pathway is necessary for the induction phase of protein synthesis-dependent synaptic plasticity. Newly synthesized proteins in dendritic shafts could be targeted selectively to activity-tagged synapses. Thus, coordinated activation of dendrite-wide translation and synaptic-specific activation is likely to be necessary for long-term synaptic plasticity. FAU - Cammalleri, Maurizio AU - Cammalleri M AD - Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. FAU - Lutjens, Robert AU - Lutjens R FAU - Berton, Fulvia AU - Berton F FAU - King, Alvin R AU - King AR FAU - Simpson, Cindy AU - Simpson C FAU - Francesconi, Walter AU - Francesconi W FAU - Sanna, Pietro Paolo AU - Sanna PP LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20031117 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Cells, Cultured MH - Dendrites/drug effects/physiology MH - Enzyme Activation MH - Hippocampus/cytology/drug effects/*physiology MH - In Vitro Techniques MH - Long-Term Potentiation/drug effects/*physiology MH - Models, Neurological MH - Protein Kinase Inhibitors MH - Protein Kinases/*physiology MH - Rats MH - Rats, Wistar MH - Ribosomal Protein S6 Kinases, 70-kDa/*physiology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases MH - Time Factors PMC - PMC283598 EDAT- 2003/11/19 05:00 MHDA- 2004/02/03 05:00 PMCR- 2004/05/25 CRDT- 2003/11/19 05:00 PHST- 2003/11/19 05:00 [pubmed] PHST- 2004/02/03 05:00 [medline] PHST- 2003/11/19 05:00 [entrez] PHST- 2004/05/25 00:00 [pmc-release] AID - 2336098100 [pii] AID - 10014368 [pii] AID - 10.1073/pnas.2336098100 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14368-73. doi: 10.1073/pnas.2336098100. Epub 2003 Nov 17.