Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved and how they are regulated are unclear. In this study, to monitor how depolarization impacts local dendritic biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling and mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming of dendritic protein expression, where changes in dendritic mRNAs and proteins are weakly correlated. For a subset of pre-localized messages, depolarization increased the translation of upstream open reading frames (uORFs) and their downstream coding sequences, enabling localized production of proteins involved in long-term potentiation, cell signaling and energy metabolism. This activity-dependent translation was accompanied by the phosphorylation and recruitment of the non-canonical translation initiation factor eIF4G2, and the translated uORFs were sufficient to confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples activity to local dendritic remodeling.

学习和记忆需要活动诱导的树突翻译变化，但涉及哪些 mRNA 以及它们是如何调节的尚不清楚。在这项研究中，为了监测去极化如何影响局部树突生物学，我们采用了树突靶向邻近标记方法，然后进行交联免疫沉淀、核糖体分析和质谱分析。用 KCl 或谷氨酸激动剂 DHPG 使原代皮质神经元去极化，引起树突蛋白表达的快速重编程，其中树突 mRNA 和蛋白的变化呈弱相关。对于预定位信息的子集，去极化增加了上游开放阅读框（uORF）及其下游编码序列的翻译，从而实现了参与长时程增强、细胞信号传导和能量代谢的蛋白质的局部产生。这种活性依赖性翻译伴随着非规范翻译起始因子 eIF4G2 的磷酸化和募集，并且翻译的 uORF 足以赋予去极化诱导的 eIF4G2 依赖性翻译控制。这些研究揭示了一种意想不到的机制，通过该机制，eIF4G2 的活性依赖性 uORF 翻译控制将活性与局部树突重塑结合起来。