Forskolin induction of late-LTP and up-regulation of 5′ TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells
Forskolin induction of late-LTP and up-regulation of 5′ TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells
复制标题
DOI：
10.1111/j.1471-4159.2008.05470.x
复制
发表时间：
2008-08-01
影响因子：
4.7
通讯作者：
Lacaille, Jean-Claude
中科院分区：
文献类型：
--
作者：
Gobert, Delphine;Topolnik, Lisa;Lacaille, Jean-Claude
长期增强（LTP）的后期阶段需要激活哺乳动物雷帕霉素靶点（mTOR）途径并合成新蛋白。mTOR通过4e结合蛋白（4e - bp）和S6K的磷酸化，以及通过选择性上调编码翻译机制成分的5‘端寡聚嘧啶（5’ TOP） mrna来调节蛋白质合成。在本研究中，我们探讨了5' TOP mrna在ltp晚期（L-LTP）中的调控。研究了大鼠器官型海马Schaffer侧枝- CA1锥体细胞突触的突触可塑性。腺苷酸环化酶激活剂Forskolin在mtor依赖的器官型切片中诱导L-LTP。为了确定5' TOP mrna是否在L-LTP期间特异性上调，我们制作了一个5' TOP-myr- dyfp报告基因来选择性地监测5' TOP翻译。在培养切片的共聚焦成像实验显示，福斯克林处理后，体细胞和树突荧光增加。这种上调依赖于完整的TOP序列，并且依赖于mTOR、细胞外信号调节激酶（ERK）和磷脂酰肌醇3-激酶（PI3K）。我们的研究结果表明，福斯克林诱导海马神经元的L-LTP，并通过mTOR上调5' TOP mrna的翻译，这表明上调翻译机制是LTP稳定的候选机制。
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.