Pharmacological brake-release of mRNA translation enhances cognitive memory

• Published in: eLife Vol. 2; p. e00498
• Main Authors: Sidrauski, Carmela, Acosta-Alvear, Diego, Khoutorsky, Arkady, Vedantham, Punitha, Hearn, Brian R, Li, Han, Gamache, Karine, Gallagher, Ciara M, Ang, Kenny K-H, Wilson, Chris, Okreglak, Voytek, Ashkenazi, Avi, Hann, Byron, Nader, Karim, Arkin, Michelle R, Renslo, Adam R, Sonenberg, Nahum, Walter, Peter
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 28-05-2013; eLife Sciences Publications, Ltd
• Subjects: Acetamides - pharmacology; Animals; ATF4; Biochemistry; Cell Biology; Cell Line; Cognition; Cognitive ability; Cyclohexylamines - pharmacology; eIF2; eIF2B; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Eukaryotic Initiation Factor-1 - antagonists & inhibitors; Eukaryotic Initiation Factor-1 - metabolism; Humans; Initiation factor eIF-2α; integrated stress response; Kinases; Memory; memory consolidation; Mice; mRNA; Neuroscience; Phosphorylation; Potassium; Protein Biosynthesis; Protein folding; Protein Kinase Inhibitors - pharmacology; RNA, Messenger - genetics; Serine; Spatial discrimination learning; Spatial memory; Transcription factors; Translation; unfolded protein response; United States > US; California; Human; unfolded protein response; eIF2B; Mouse; Rat; memory consolidation; ATF4; eIF2; integrated stress response
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.00498

Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. DOI:http://dx.doi.org/10.7554/eLife.00498.001.