Translational control of hippocampal synaptic plasticity and memory by the eIF2α kinase GCN2
Translational control of hippocampal synaptic plasticity and memory by the eIF2α kinase GCN2
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DOI：
10.1038/nature03897
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发表时间：
2005-08-25
期刊：
影响因子：
64.8
通讯作者：
Sonenberg, N
中科院分区：
文献类型：
--
作者：
Costa-Mattioli, M;Gobert, D;Sonenberg, N
对各种形式的突触可塑性的研究表明，信使RNA翻译与学习和记忆之间存在联系。与记忆一样，突触可塑性包括一个依赖于对已有蛋白质进行修饰的早期阶段，以及一个需要转录和合成新蛋白质的晚期阶段（1,2）。突触后靶点的激活似乎会触发可塑性相关基因的转录。新的信使RNA要么在胞体中翻译，要么在翻译前被运输到突触。GCN2是一种关键的蛋白激酶，它调节翻译的起始。在此我们报道了GCN2基因敲除（-/-）小鼠海马脑片的一个独特特征：在CA1区，单次100赫兹的刺激序列可诱导出强烈且持续的长时程增强作用（晚期长时程增强，即L - LTP），这依赖于转录和翻译。相比之下，在野生型脑片中能诱发L - LTP的刺激，如四次100赫兹的刺激序列或毛喉素，在GCN2基因敲除（-/-）脑片中无法诱发L - LTP。这种异常的突触可塑性在莫里斯水迷宫中GCN2基因敲除（-/-）小鼠的行为上有所体现：经过轻度训练后，它们的空间记忆增强，但经过更强烈的训练后则受损。活化的GCN2刺激ATF4的信使RNA翻译，ATF4是环磷腺苷酸反应元件结合蛋白（CREB）的拮抗剂。因此，在GCN2基因敲除（-/-）小鼠的海马中，ATF4的表达降低，而CREB的活性增加。我们的研究提供了遗传学、生理学、行为学和分子学方面的证据，表明GCN2通过调节ATF4/CREB通路来调控突触可塑性以及学习和记忆。
Studies on various forms of synaptic plasticity have shown a link between messenger RNA translation, learning and memory. Like memory, synaptic plasticity includes an early phase that depends on modification of pre-existing proteins, and a late phase that requires transcription and synthesis of new proteins(1,2). Activation of postsynaptic targets seems to trigger the transcription of plasticity-related genes. The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation. Here we report a unique feature of hippocampal slices from GCN2(-/-) mice: in CA1, a single 100-Hz train induces a strong and sustained long-termpotentiation ( late LTP or L-LTP), which is dependent on transcription and translation. In contrast, stimulation that elicits L-LTP in wild-type slices, such as four 100-Hz trains or forskolin, fails to evoke L-LTP in GCN2(-/-) slices. This aberrant synaptic plasticity is mirrored in the behaviour of GCN2(-/-) mice in the Morris water maze: after weak training, their spatial memory is enhanced, but it is impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4, an antagonist of cyclic-AMP-response-element-binding protein ( CREB). Thus, in the hippocampus of GCN2(-/-) mice, the expression of ATF4 is reduced and CREB activity is increased. Our study provides genetic, physiological, behavioural and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory, through modulation of the ATF4/CREB pathway.