The ISR downstream target ATF4 represses long- term memory in a cell type-specific manner

• 成果类型: Article
• 署名作者: Mahmood, Niaz; Choi, Jung- Hyun; Wu, Pei You; Dooling, Sean W.; Watkins, Trent A.; Huang, Ziying; Lipman, Jesse; Zhao, Hanjie; Yang, Anqi; Silversmith, Jake; Inglebert, Yanis; Koumenis, Constantinos; Sharma, Vijendra; Lacaille, Jean- Claude; Sossin, Wayne S.; Khoutorsky, Arkady; Mckinney, R. Anne; Costa-Mattioli, Mauro; Sonenberg, Nahum
• 署名单位: McGill University; McGill University; McGill University; Baylor College of Medicine; Universite de Montreal; University of Pennsylvania; University of Windsor; McGill University; McGill University; McGill University; McGill University; Baylor College of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9994
• DOI: 10.1073/pnas.2407472121
• 发表日期: 2024-07-30
• 关键词: morris water maze; synaptic plasticity; intellectual disability; translational control; potentiation; expression; Mutation; protein; stress; forms

摘要

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), 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.