Forskolin induction of late-LTP and up-regulation of 5' TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells.
The late phase of long-term potentiation (LTP) requires activation of the mammalian target of rapamycin (mTOR) pathway and synthesis of new proteins. mTOR regulates protein synthesis via phosphorylation of 4E-binding proteins (4E-BPs) and S6K, and via selective up-regulation of 5' terminal oligopyrimidine (5' TOP) mRNAs that encode components of the translational machinery. In this study, we explored the regulation of 5' TOP mRNAs during late-LTP (L-LTP). Synaptic plasticity was studied at Schaffer collateral--CA1 pyramidal cell synapses in rat organotypic hippocampal slices. Forskolin, an adenylate cyclase activator, induced L-LTP in organotypic slices that was mTOR-dependent. To determine if 5' TOP mRNAs are specifically up-regulated during L-LTP, we generated a 5' TOP-myr-dYFP reporter to selectively monitor 5' TOP translation. Confocal imaging experiments in cultured slices revealed an increase in somatic and dendritic fluorescence after forskolin treatment. This up-regulation was dependent on an intact TOP sequence and was mTOR, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)-dependent. Our findings indicate that forskolin induces L-LTP in hippocampal neurons and up-regulates 5' TOP mRNAs translation via mTOR, suggesting that up-regulation of the translational machinery is a candidate mechanism for the stabilization of LTP.
Gobert
Delphine
D
Département de Physiologie, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, QC, Canada.
Topolnik
Lisa
L
Azzi
Mounia
M
Huang
Linda
L
Badeaux
Frédérique
F
Desgroseillers
Luc
L
Sossin
Wayne S
WS
Lacaille
Jean-Claude
JC
D000818:Animals; D005576:Colforsin / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D038641:RNA 5' Terminal Oligopyrimidine Sequence / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D005576:Colforsin; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat