Activation of the phosphoinositide 3-kinase-akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression
Activation of the phosphoinositide 3-kinase-akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression
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DOI：
10.1523/jneurosci.0995-04.2004
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发表时间：
2004-07-14
影响因子：
5.3
通讯作者：
Klann, E
中科院分区：
文献类型：
--
作者：
Hou, LF;Klann, E
海马长期抑制（LTD）是一种突触强度的长期下降，最常研究的是海马区CA1锥体细胞的谷氨酸能输入。药理激动剂(RS)-3,5-二羟基苯基甘氨酸（DHPG）激活g蛋白偶联I组（包括1型和5型）代谢性谷氨酸受体（mGluRs）可引起海马CA1区LTD。最近的报道表明，dhpg诱导的LTD需要从头合成蛋白质。然而，我们对mGluRs与翻译起始之间的信号通路知之甚少。在这项研究中，我们研究了DHPG诱导的mGluR-LTD是否需要激活磷酸化肌肽3-激酶(PI3K) - akt -哺乳动物雷帕霉素靶蛋白（mTOR）途径，该途径已被证明可以调节翻译起始。我们发现，将小鼠海马切片与DHPG短暂孵育后，海马CA1区Akt和mTOR的磷酸化水平升高。两种结构无关的PI3K抑制剂LY294002和wortmannin阻断了dhpg诱导的Akt和mTOR磷酸化的增加。生化分离研究表明，dhpg诱导的突触eurosome制剂中Akt和mTOR磷酸化水平升高，免疫组织化学分析显示，CA1区锥体层和辐射层均可检测到类似的磷酸化水平升高。最后，我们观察到PI3K抑制剂和雷帕霉素（一种mTOR抑制剂）都能阻止DHPG诱导的mGluR-LTD。总之，我们的研究结果表明，mGluR-LTD需要激活pi3k - akt - mtor信号级联，并表明该途径可能将I组mglur与海马区CA1的翻译起始结合起来。
Hippocampal long-term depression (LTD) is a long-lasting decrease in synaptic strength that is most commonly studied at glutamatergic inputs to pyramidal cells in hippocampal area CA1. Activation of G-protein-coupled group I ( including types 1 and 5) metabotropic glutamate receptors ( mGluRs) by the pharmacological agonist (RS)-3,5-dihydroxyphenylglycine ( DHPG) elicits LTD in area CA1 of the hippocampus. Recent reports have shown that de novo protein synthesis is necessary for DHPG-induced LTD. However, relatively little is known about the signaling pathways that couple mGluRs to translation initiation. In this study, we investigated whether the activation of the phosphoinositide 3-kinase (PI3K) -Akt-mammalian target of rapamycin ( mTOR) pathway, which has been shown to regulate translation initiation, is necessary for mGluR-LTD induced by DHPG. We found that brief incubations of mouse hippocampal slices with DHPG resulted in increased phosphorylation of Akt and mTOR in hippocampal area CA1. Two structurally unrelated PI3K inhibitors, LY294002 and wortmannin, blocked the DHPG-induced increases in phosphorylation of Akt and mTOR. Biochemical fractionation studies showed that the DHPG-induced increase in the phosphorylation of Akt and mTOR could be detected in synaptoneurosome preparations, and immunohistochemical analysis revealed that similar increases could be detected in both stratum pyramidale and stratum radiatum in area CA1. Finally, we observed that both PI3K inhibitors and rapamycin, an mTOR inhibitor, prevented mGluR-LTD induced by DHPG. Together, our findings indicate that activation of thePI3K-Akt-mTOR signaling cascade is required for mGluR-LTD and suggest that this pathway may couple group I mGluRs to translation initiation in hippocampal area CA1.