An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1-4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5-10. One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF211. Phosphorylation of the α-subunit of eIF2 (p-eIF2α), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds11-13. By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14-17, or mimicking reduced p-eIF2α with the ISR inhibitor ISRIB11, enhances long-term memory in health and disease18. Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces eIF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2α in either excitatory or somatostatin-expressing (but not parvalbumin-expressing) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.

中文翻译：

---

eIF2α 通过兴奋性神经元和生长抑素神经元控制记忆巩固

学习和记忆的一个重要原则是促进长期记忆形成的分子开关的概念1-4。蛋白质稳态的调节是新记忆巩固的关键和限速步骤5-10。增强记忆最有效和最普遍的方法之一是调节由翻译起始因子 eIF211 控制的蛋白质的合成。eIF2 的 α 亚基 (p-eIF2α) 是综合应激反应 (ISR) 的核心组成部分，其磷酸化会损害啮齿动物和鸟类的长期记忆形成11-13。相比之下，通过突变 eIF2α 磷酸化位点、从基因上 11 和药理学上抑制 ISR 激酶 14-17 或用 ISR 抑制剂 ISRIB11 模拟还原的 p-eIF2α 来抑制 ISR，可以增强健康和疾病中的长期记忆 18。在这里，我们使用分子遗传学来剖析 ISR 控制认知处理的神经元回路。我们发现学习会降低海马兴奋性神经元和海马抑制性神经元（表达生长抑素但不表达小清蛋白的神经元）的 eIF2α 磷酸化。此外，在兴奋性或表达生长抑素（但不表达小清蛋白）的抑制性神经元中消除 p-eIF2α 会增加一般 mRNA 翻译，增强突触可塑性并增强长期记忆。因此，eIF2α依赖性mRNA翻译通过兴奋性神经元和表达生长抑素的抑制性神经元的自主机制控制记忆巩固。