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

Abstract

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. © 2008 The Authors.