Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada.
Proc Natl Acad Sci U S A. 2024 Jul 30;121(31):e2407472121. doi: 10.1073/pnas.2407472121. Epub 2024 Jul 24.
The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons.
综合应激反应（ISR）是一个关键的蛋白质稳态网络，在长时记忆（LTM）的形成中起着关键作用。ISR 控制 LTM 的精确机制尚不清楚。在这里，我们报告了关于 ISR 如何通过靶向敲除应激反应的关键下游效应因子激活转录因子 4（ATF4）来调节记忆过程的见解，该基因在各种神经元和非神经元细胞类型中都有表达。我们发现，从大脑前兴奋性神经元中去除 ATF4（但不是从抑制性神经元、胆碱能神经元或星形胶质细胞中去除）会增强 LTM 的形成。此外，兴奋性神经元中 ATF4 的缺失降低了长时程增强（LTP）的诱导阈值，LTP 是 LTM 的细胞模型。转录组学和蛋白质组学分析显示，兴奋性神经元中 ATF4 的缺失会导致氧化磷酸化途径的关键组成部分上调，这些组成部分对 ATP 的产生至关重要。因此，我们得出结论，ATF4 作为记忆抑制剂选择性地在兴奋性神经元中发挥作用。
