Language
English
Publication Date
7-30-2024
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.2407472121
PMID
39047038
PMCID
PMC11295034
PubMedCentral® Posted Date
7-24-2024
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Animals, Mice, Activating Transcription Factor 4, Astrocytes, Long-Term Potentiation, Memory, Long-Term, Mice, Knockout, Neurons, Prosencephalon, Male, integrated stress response, learning and memory, synaptic plasticity, protein synthesis
Published Open-Access
yes
Recommended Citation
Mahmood, Niaz; Choi, Jung-Hyun; Wu, Pei You; et al., "The ISR Downstream Target ATF4 Represses Long-Term Memory in a Cell Type-Specific Manner" (2024). Faculty, Staff and Students Publications. 7260.
https://digitalcommons.library.tmc.edu/baylor_docs/7260