eIF2α controls memory consolidation via excitatory and somatostatin neurons

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dc.contributor.authorSharma, Vijendraen
dc.contributor.authorSood, Rapitaen
dc.contributor.authorKhlaifia, Abdessattaren
dc.contributor.authorEslamizade, Mohammad Javaden
dc.contributor.authorHung, Tzu-Yuen
dc.contributor.authorLou, Danningen
dc.contributor.authorAsgarihafshejani, Azamen
dc.contributor.authorLalzar, Mayaen
dc.contributor.authorKiniry, Stephen J.en
dc.contributor.authorStokes, Matthew P.en
dc.contributor.authorCohen, Noahen
dc.contributor.authorNelson, Alissa J.en
dc.contributor.authorAbell, Kathrynen
dc.contributor.authorPossemato, Anthony P.en
dc.contributor.authorGal-Ben-Ari, Shuniten
dc.contributor.authorTruong, Vinh T.en
dc.contributor.authorWang, Pengen
dc.contributor.authorYiannakas, Adonisen
dc.contributor.authorSaffarzadeh, Fatemehen
dc.contributor.authorCuello, A. Claudioen
dc.contributor.authorNader, Karimen
dc.contributor.authorKaufman, Randal J.en
dc.contributor.authorCosta-Mattioli, Mauroen
dc.contributor.authorBaranov, Pavel V.en
dc.contributor.authorQuintana, Alberten
dc.contributor.authorSanz, Elisendaen
dc.contributor.authorKhoutorsky, Arkadyen
dc.contributor.authorLacaille, Jean-Claudeen
dc.contributor.authorRosenblum, Kobien
dc.contributor.authorSonenberg, Nahumen
dc.contributor.funderInternational Development Research Centreen
dc.contributor.funderAzrieli Foundationen
dc.contributor.funderCanadian Institutes of Health Researchen
dc.contributor.funderIsrael Science Foundationen
dc.contributor.funderNational Institutes of Healthen
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidadesen
dc.contributor.funderEuropean Research Councilen
dc.contributor.funderMinisterio de Economía y Competitividaden
dc.contributor.funderAgència de Gestió d’Ajuts Universitaris i de Recercaen
dc.contributor.funderNational Institute of Neurological Disorders and Strokeen
dc.contributor.funderRichard and Edith Strauss Foundationen
dc.date.accessioned2023-05-24T16:05:48Z
dc.date.available2023-05-24T16:05:48Z
dc.date.issued2020-10-07en
dc.description.abstractAn important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1,2,3,4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5,6,7,8,9,10. 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 birds11,12,13. By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14,15,16,17, 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.en
dc.description.sponsorshipCanadian Institutes of Health Research (PJT-153311; Canada Research Chair in Cellular and Molecular Neurophysiology (CRC-950-231066)); National Institutes of Health (R01 DK113171; R01 DK103185; R01 CA198103; R01 AG062190); Ministerio de Ciencia, Innovación y Universidades (RTI2018-101838-J-I00); European Research Council (ERC-2014-StG-638106); Ministerio de Economía y Competitividad (SAF2017-88108-R); Agència de Gestió d’Ajuts Universitaris i de Recerca (2017SGR- 323); National Institute of Neurological Disorders and Stroke (2R01 NS076708-06 NINDS); Richard and Edith Strauss Foundation (Postdoctoral Fellowships in Medicine)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSharma, V., Sood, R., Khlaifia, A., et al (2020) 'eIF2α controls memory consolidation via excitatory and somatostatin neurons', Nature 586, pp. 412-416. doi: 10.1038/s41586-020-2805-8en
dc.identifier.doi10.1038/s41586-020-2805-8en
dc.identifier.eissn1476-4687en
dc.identifier.endpage416en
dc.identifier.issn0028-0836en
dc.identifier.journaltitleNatureen
dc.identifier.startpage412en
dc.identifier.urihttps://hdl.handle.net/10468/14510
dc.identifier.volume586en
dc.language.isoenen
dc.publisherNature Researchen
dc.rights© 2020, The Authors, under exclusive licence to Springer Nature Limited. This is a post-peer-review, pre-copyedit version of a paper published as: Sharma, V., Sood, R., Khlaifia, A., et al (2020) 'eIF2α controls memory consolidation via excitatory and somatostatin neurons', Nature 586, pp. 412-416, doi: 10.1038/s41586-020-2805-8. The final authenticated version is available online at: https://doi.org/10.1038/s41586-020-2805-8en
dc.subjecteIF2αen
dc.subjectMemoryen
dc.subjectExcitatory and somatostatin neuronsen
dc.titleeIF2α controls memory consolidation via excitatory and somatostatin neuronsen
dc.typeArticle (peer-reviewed)en
oaire.citation.issue7829en
oaire.citation.volume586en
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