Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation.
Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation.
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DOI：
10.1186/s13041-017-0330-y
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发表时间：
2017-10-30
期刊：
影响因子：
3.6
通讯作者：
Sutton MA
中科院分区：
文献类型：
--
作者：
Henry FE;Hockeimer W;Chen A;Mysore SP;Sutton MA
海马区兴奋性突触强度的变化被认为在哺乳动物大脑中存储和回忆新信息方面起着至关重要的作用。这些变化涉及树突棘的功能和形态特征的调节，树突棘是兴奋性突触接触的主要部位。新的蛋白质合成被广泛地涉及到长时程增强(LTP)后观察到的功能变化，类似地，突触增强后脊柱形态的变化也被广泛地记录下来。然而，从头翻译和强化脊椎的结构变化之间的机械联系还不太清楚。在这里，我们明确地评估了在雷帕霉素机械靶点(MTOR)控制下的新蛋白质翻译对LTP相关脊柱形态变化的潜在贡献。利用遗传和药物操作mTORC1功能结合共聚焦显微镜在活体分离的海马区培养，我们证明了化学诱导的LTP(CLTP)需要从头开始蛋白质合成和完整的mTORC1信号。我们观察到不同形态类别的反应特性有显著的差异，蘑菇刺对不同水平的突触活动中改变的mTORC1信号表现出特别的敏感性。值得注意的是，虽然对mTORC1信号的药物抑制显著地减少了甘氨酸引起的脊柱形态的变化，但mTORC1信号的瞬时遗传上调不足以单独产生脊柱增大。相反，当结合其他亚阈值突触刺激时，mTORC1信号的遗传上调促进了脊柱头部直径的快速扩张。这些结果表明，突触活性衍生的信号通路与mTORC1依赖的翻译控制机制相结合，最终调节脊柱形态的变化。由于几种与自闭症和智能障碍有关的单基因神经发育障碍共享mTORC1信号异常的共同特征，进一步了解这一信号通路在调节突触功能和形态中的作用将对开发新的治疗干预措施至关重要。
Alterations in the strength of excitatory synapses in the hippocampus is believed to serve a vital function in the storage and recall of new information in the mammalian brain. These alterations involve the regulation of both functional and morphological features of dendritic spines, the principal sites of excitatory synaptic contact. New protein synthesis has been implicated extensively in the functional changes observed following long-term potentiation (LTP), and changes to spine morphology have similarly been documented extensively following synaptic potentiation. However, mechanistic links between de novo translation and the structural changes of potentiated spines are less clear. Here, we assess explicitly the potential contribution of new protein translation under control of the mechanistic target of rapamycin (mTOR) to LTP-associated changes in spine morphology. Utilizing genetic and pharmacological manipulations of mTORC1 function in combination with confocal microscopy in live dissociated hippocampal cultures, we demonstrate that chemically-induced LTP (cLTP) requires do novo protein synthesis and intact mTORC1 signaling. We observed a striking diversity in response properties across morphological classes, with mushroom spines displaying a particular sensitivity to altered mTORC1 signaling across varied levels of synaptic activity. Notably, while pharmacological inhibition of mTORC1 signaling significantly diminished glycine-induced changes in spine morphology, transient genetic upregulation of mTORC1 signaling was insufficient to produce spine enlargements on its own. In contrast, genetic upregulation of mTORC1 signaling promoted rapid expansion in spine head diameter when combined with otherwise sub-threshold synaptic stimulation. These results suggest that synaptic activity-derived signaling pathways act in combination with mTORC1-dependent translational control mechanisms to ultimately regulate changes in spine morphology. As several monogenic neurodevelopmental disorders with links to Autism and Intellectual Disability share a common feature of dysregulated mTORC1 signaling, further understanding of the role of this signaling pathway in regulating synapse function and morphology will be essential in the development of novel therapeutic interventions.
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影响因子：
64.8
作者：
Hedrick NG;Harward SC;Hall CE;Murakoshi H;McNamara JO;Yasuda R
通讯作者：
Yasuda R
影响因子：
64.8
作者：
Lee, Seok-Jin R.;Escobedo-Lozoya, Yasmin;Szatmari, Erzsebet M.;Yasuda, Ryohei
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作者：
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3.3
作者：
Fraser, M. M.;Bayazitov, I. T.;Baker, S. J.
通讯作者：
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影响因子：
64.8
作者：
Bingol, Baris;Schuman, Erin M.
通讯作者：
Schuman, Erin M.