Center for Neural Science, New York University, New York, New York 10003.
Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York 12208.
J Neurosci. 2021 Feb 3;41(5):947-959. doi: 10.1523/JNEUROSCI.2284-20.2020. Epub 2020 Dec 9.
Long-term memory (LTM) formation is a critical survival process by which an animal retains information about prior experiences to guide future behavior. In the experimentally advantageous marine mollusk , LTM for sensitization can be induced by the presentation of two aversive shocks to the animal's tail. Each of these training trials recruits distinct growth factor signaling systems that promote LTM formation. Specifically, whereas intact TrkB signaling during Trial 1 promotes an initial and transient increase of the immediate early gene mRNA, a prolonged increase in gene expression required for LTM formation requires the addition of TGFβ signaling during Trial 2. Here we explored the molecular mechanisms by which Trial 2 achieves the essential prolonged gene expression of We find that this prolonged gene expression is not dependent on transcription, but that mRNA synthesized by Trial 1 is post-transcriptionally stabilized by interacting with the RNA-binding protein ApELAV. This interaction is promoted by p38 MAPK activation initiated by TGFβ. We further demonstrate that blocking the interaction of ApELAV with its target mRNA during Trial 2 blocks both the prolonged increase in gene expression and the behavioral induction of LTM. Collectively, our findings elucidate both when and how ELAV proteins are recruited for the stabilization of mRNA in LTM formation. Stabilization of a transiently expressed immediate early gene mRNA by a repeated training trial may therefore serve as a "filter" for learning, permitting only specific events to cause lasting transcriptional changes and behavioral LTM. In the present paper, we significantly extend the general field of molecular processing in long-term memory (LTM) by describing a novel form of pretranslational processing required for LTM, which relies on the stabilization of a newly synthesized mRNA by a class of RNA binding proteins (ELAVs). There are now compelling data showing that important processing can occur after transcription of a gene, but before translation of the message into protein. Although the potential importance of ELAV proteins in LTM formation has previously been reported, the specific actions of ELAV proteins during LTM formation remained to be understood. Our new findings thus complement and extend this literature by demonstrating when and how this post-transcriptional gene regulation is mediated in the induction of LTM.
长期记忆（LTM）的形成是动物保留先前经验信息以指导未来行为的关键生存过程。在实验有利的海洋软体动物中，通过向动物的尾巴施加两次厌恶刺激，可以诱导对敏感化的 LTM。这些训练试验中的每一个都招募了不同的生长因子信号系统，促进 LTM 的形成。具体而言，虽然在试验 1 中完整的 TrkB 信号促进了即时早期基因 mRNA 的初始和短暂增加，但对于 LTM 形成所需的延长的基因表达增加，需要在试验 2 中添加 TGFβ信号。在这里，我们探讨了试验 2 实现 基因表达延长的分子机制。我们发现，这种延长的基因表达不依赖于转录，但由试验 1 合成的 mRNA 通过与 RNA 结合蛋白 ApELAV 相互作用而被稳定。这种相互作用是由 TGFβ引发的 p38 MAPK 激活所促进的。我们进一步证明，在试验 2 期间阻断 ApELAV 与其靶 mRNA 的相互作用会阻止 基因表达的延长增加和 LTM 的行为诱导。总的来说，我们的研究结果阐明了 ELAV 蛋白何时以及如何被招募用于 LTM 形成中的 mRNA 稳定。因此，通过重复训练试验稳定瞬时表达的即时早期基因 mRNA 可以作为学习的“过滤器”，仅允许特定事件引起持久的转录变化和行为 LTM。在本文中，我们通过描述一种新的 LTM 所必需的翻译前加工形式，极大地扩展了长期记忆（LTM）的分子处理的一般领域，该形式依赖于一类 RNA 结合蛋白（ELAVs）对新合成的 mRNA 的稳定。现在有令人信服的数据表明，在基因转录后但在信息翻译成蛋白质之前，可以发生重要的加工。虽然 ELAV 蛋白在 LTM 形成中的重要性以前已经被报道过，但在 LTM 形成过程中 ELAV 蛋白的具体作用仍有待了解。我们的新发现因此通过证明在 LTM 的诱导中这种转录后基因调控是如何介导的，补充和扩展了这一文献。
