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 Cuello, Karim Nader, Randal J. Kaufman, Mauro Costa-Mattioli, Pavel V. Baranov, Albert Quintana, Elisenda Sanz, Arkady Khoutorsky, Jean-Claude Lacaille, Kobi Rosenblum () and Nahum Sonenberg ()
Additional contact information
Vijendra Sharma: McGill University
Rapita Sood: McGill University
Abdessattar Khlaifia: University of Montréal
Mohammad Javad Eslamizade: McGill University
Tzu-Yu Hung: McGill University
Danning Lou: McGill University
Azam Asgarihafshejani: University of Montréal
Maya Lalzar: University of Haifa
Stephen J. Kiniry: University College Cork
Matthew P. Stokes: Proteomics Division, Cell Signaling Technology
Noah Cohen: McGill University
Alissa J. Nelson: Proteomics Division, Cell Signaling Technology
Kathryn Abell: Proteomics Division, Cell Signaling Technology
Anthony P. Possemato: Proteomics Division, Cell Signaling Technology
Shunit Gal-Ben-Ari: University of Haifa
Vinh T. Truong: McGill University
Peng Wang: McGill University
Adonis Yiannakas: University of Haifa
Fatemeh Saffarzadeh: University of Montréal
A. Claudio Cuello: McGill University
Karim Nader: McGill University
Randal J. Kaufman: Sanford-Burnham-Prebys Medical Discovery Institute
Mauro Costa-Mattioli: Baylor College of Medicine
Pavel V. Baranov: University College Cork
Albert Quintana: Universitat Autònoma de Barcelona
Elisenda Sanz: Universitat Autònoma de Barcelona
Arkady Khoutorsky: McGill University
Jean-Claude Lacaille: University of Montréal
Kobi Rosenblum: University of Haifa
Nahum Sonenberg: McGill University

Nature, 2020, vol. 586, issue 7829, 412-416

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2805-8

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