eIF2α controls memory consolidation via excitatory and somatostatin neurons

Vijendra Sharma, Rapita Sood, Abdessattar Khlaifia, Mohammad Javad Eslamizade, Tzu Yu Hung, Danning Lou, Azam Asgarihafshejani, Maya Lalzar, Stephen J. Kiniry, Matthew P. Stokes, Noah Cohen, Alissa J. Nelson, Kathryn Abell, Anthony P. Possemato, Shunit Gal-Ben-Ari, Vinh T. Truong, Peng Wang, Adonis Yiannakas, Fatemeh Saffarzadeh, A. Claudio CuelloKarim Nader, Randal J. Kaufman, Mauro Costa-Mattioli, Pavel V. Baranov, Albert Quintana, Elisenda Sanz, Arkady Khoutorsky, Jean Claude Lacaille, Kobi Rosenblum, Nahum Sonenberg

Research output: Contribution to journalArticlepeer-review


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 of the 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 eIF2 (p-eIF2α), 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 eIF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14–17, or mimicking reduced p-eIF2α 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 eIF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2α 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, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.

Original languageAmerican English
Pages (from-to)412-416
Number of pages5
Issue number7829
StatePublished - 15 Oct 2020

All Science Journal Classification (ASJC) codes

  • General


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