eIF2a controls memory consolidation via excitatory and somatostatin neurons

• Published in: Nature (London) 2020-10, Vol.586 (7829), p.412-3
• Main Authors: Sharma, Vijendra, Sood, Rapita, Khlaifia, Abdessattar, Eslamizade, Mohammad Javad, Hung, Tzu-Yu, Lou, Danning, Asgarihafshejani, Azam, Lalzar, Maya, Kiniry, Stephen J, Stokes, Matthew P, Cohen, Noah, Nelson, Alissa J, Abell, Kathryn, Possemato, Anthony P, Gal-Ben-Ari, Shunit, Truong, Vinh T, Wang, Peng, Yiannakas, Adonis, Saffarzadeh, Fatemeh, Cuello, A Claudio, Nader, Karim, Kaufman, Randal J, Costa-Mattioli, Mauro, Baranov, Pavel V, Quintana, Albert, Sanz, Elisenda, Khoutorsky, Arkady, Lacaille, Jean-Claude, Rosenblum, Kobi, Sonenberg, Nahum
• Format: Article
• Language: English
• Subjects: Ablation; Cognitive ability; Consolidation; Genetics; Hippocampus; Information processing; Initiation factor eIF-2; Kinases; Learning; Long term memory; Memory; Mimicry; Molecular machines; mRNA; Neurons; Parvalbumin; Phosphorylation; Protein synthesis; Proteins; Rodents; Somatostatin; Synaptic plasticity
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2805-8

An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1-4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5-10. One ofthe most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF211. Phosphorylation of the α-subunit of elF2 (p-elF2α), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds11-13. By contrast, inhibiting the ISR by mutating the elF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14-17, or mimicking reduced p-elF2α with the ISR inhibitor ISRIB11, enhances long-term memory in health and disease18. Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces elF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-elF2α in either excitatory or somatostatin-expressing (but not parvalbumin-expressing) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, elF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.