@article{e75ed57c385b4e909954d277bfe6a742,
title = "Cell-type-specific drug-inducible protein synthesis inhibition demonstrates that memory consolidation requires rapid neuronal translation",
abstract = "New protein synthesis is known to be required for the consolidation of memories, yet existing methods of blocking translation lack spatiotemporal precision and cell-type specificity, preventing investigation of cell-specific contributions of protein synthesis. Here we developed a combined knock-in mouse and chemogenetic approach for cell-type-specific drug-inducible protein synthesis inhibition that enables rapid and reversible phosphorylation of eukaryotic initiation factor 2α, leading to inhibition of general translation by 50% in vivo. We use cell-type-specific drug-inducible protein synthesis inhibition to show that targeted protein synthesis inhibition pan-neuronally and in excitatory neurons in the lateral amygdala (LA) impaired long-term memory. This could be recovered with artificial chemogenetic activation of LA neurons, although at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eukaryotic initiation factor 2α in excitatory neurons in the LA enhanced memory strength but reduced memory fidelity and behavioral flexibility. Our findings provide evidence for a cell-specific translation program during consolidation of threat memories.",
author = "Prerana Shrestha and Pinar Ayata and Pedro Herrero-Vidal and Francesco Longo and Alexandra Gastone and LeDoux, {Joseph E.} and Nathaniel Heintz and Eric Klann",
note = "Funding Information: We thank M. Marmacz for expert technical assistance, C. Rice (The Rockefeller University) for providing the plasmid for HCV polyprotein, M. Ryan (University of St Andrews) for the 2A plasmid, A. Klinakis (Biomedical Research Foundation Academy of Athens), A. Domingos and J. Friedman (The Rockefeller University) for the plasmid containing the STOP sequence and the Eef1a1 targeting plasmid, P. Vandenabeele (Ghent University) for the PKRk plasmid, R. Kaufman (Sanford Burnham Prebys Medical Discovery Institute) for the Eif2s1 (S51A); CAG Prfl.Eif2s1.fl.GFP mouse line and J. Pelletier (McGill University) for the Col1a1TRE GFP.shmir4E.389 mouse line. We thank the Allen Brain Institute for providing AAV.CAG Pr.DIO.tTA. We thank all members of the Klann laboratory for critical feedback and discussions. This study was supported by National Institute of Health Grants (nos. NS034007 and NS047384) to E.K., a Howard Hughes Medical Investigator grant to N.H. and a Brain and Behavior Research Foundation NARSAD Young Investigator grant to P.S. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = feb,
day = "1",
doi = "10.1038/s41593-019-0568-z",
language = "English (US)",
volume = "23",
pages = "281--292",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "2",
}