Center for Neural Science, New York University, New York, New York 10003.
Center for Neural Science, New York University, New York, New York 10003
J Neurosci. 2014 Jul 2;34(27):9034-9. doi: 10.1523/JNEUROSCI.0878-14.2014.
Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)-eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2-nitrophenyl)]propionic acid), an inhibitor of eFI4E-eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E-eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted in memory destabilization 10 d after reactivation, whereas inhibition of eIF4E-eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence of memory at longer intervals after memory reactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence.
记忆提取，通常称为再巩固，可以使先前巩固的记忆易受操纵，从而导致记忆强度的改变。虽然已经知道再巩固需要哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）依赖性翻译，但再巩固中其下游效应物的具体贡献尚不清楚。我们使用小鼠听觉恐惧条件反射来研究真核起始因子 4E（eIF4E）-eIF4G 相互作用和 p70 S6 激酶多肽 1（S6K1）在再巩固中的作用。我们发现，eIF4E-eIF4G 相互作用的抑制剂 4EGI-1[2-[(4-(3,4-二氯苯基)-噻唑-2-基)肼基]-3-(2-硝基苯基)]丙酸]或 S6K1 的抑制剂 PF-4708671[2-((4-(5-乙基嘧啶-4-基)哌嗪-1-基)甲基)-5-(三氟甲基)-1H-苯并[d]咪唑]，单独使用时均不能阻断听觉恐惧记忆的再巩固。相比之下，在记忆再激活后立即同时使用这些药物来阻断 eIF4E-eIF4G 相互作用和 S6K1，显著减弱了恐惧记忆的再巩固。此外，在记忆再激活 10d 后，4EGI-1 和 PF-4708671 的组合进一步使恐惧记忆不稳定，这与使用 mTORC1 抑制剂雷帕霉素的实验结果一致。此外，在检索后立即抑制 S6K1 会导致再激活 10d 后记忆不稳定，而抑制 eIF4E-eIF4G 相互作用则不会。这些结果表明，恐惧记忆的再巩固需要 eIF4E 与 eIF4G 以及 S6K1 活性的同时关联，并且在记忆再激活后较长时间间隔内记忆的持续存在也需要涉及 S6K1 的 mTORC1 依赖性过程。这些发现为 mTORC1 依赖性翻译如何精细调节改变记忆持久性提供了潜在机制。
