Forskolin induction of late‐LTP and up‐regulation of 5′ TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells

• Published in: Journal of neurochemistry 2008-08, Vol.106 (3), p.1160-1174
• Main Authors: Gobert, Delphine, Topolnik, Lisa, Azzi, Mounia, Huang, Linda, Badeaux, Frédérique, DesGroseillers, Luc, Sossin, Wayne S., Lacaille, Jean‐Claude
• Format: Article
• Language: English
• Subjects: 5′ terminal oligopyrimidine tract mRNAs; Animals; Biochemistry; Brain; Cellular biology; Colforsin - pharmacology; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - physiology; Hippocampus - drug effects; Hippocampus - physiology; Humans; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Male; mammalian target of rapamycin; Neurology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - physiology; Protein Biosynthesis - drug effects; Protein Biosynthesis - physiology; Protein Kinases - biosynthesis; Protein Kinases - genetics; Protein Kinases - physiology; Protein synthesis; Pyramidal Cells - drug effects; Pyramidal Cells - enzymology; Pyramidal Cells - physiology; Rats; Rats, Sprague-Dawley; RNA 5' Terminal Oligopyrimidine Sequence - drug effects; RNA 5' Terminal Oligopyrimidine Sequence - physiology; Rodents; synaptic plasticity; TOR Serine-Threonine Kinases; translation; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05470.x

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.