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

作者：Gobert Delphine; Topolnik Lisa; Azzi Mounia; Huang Linda; Badeaux Frederique; DesGroseillers Luc; Sossin Wayne S; Lacaille Jean Claude^*

来源：Journal of Neurochemistry, 2008, 106(3): 1160-1174.

DOI：10.1111/j.1471-4159.2008.05470.x

• 5 ' terminal oligopyrimidine tract mRNAs
• mammalian target of rapamycin
• synaptic plasticity
• translation

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.

• 出版日期2008-8