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; Nahum Sonenberg

doi:10.1038/s41586-020-2805-8

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

Department of Neurobiology

Research output: Contribution to journal › Article › peer-review

Abstract

An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory^1–4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories^5–10. 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 birds^11–13. By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically¹¹ and pharmacologically inhibiting the ISR kinases^14–17, 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 language	English
Pages (from-to)	412-416
Number of pages	5
Journal	Nature
Volume	586
Issue number	7829
DOIs	https://doi.org/10.1038/s41586-020-2805-8
State	Published - 15 Oct 2020

Bibliographical note

Funding Information:
Acknowledgements This study was supported by a Canada’s International Development Research Centre (IDRC), in partnership with the Azrieli Foundation, the Canadian Institutes of Health Research (CIHR), and the Israel Science Foundation (ISF) to K.R. and N.S. J.-C.L. is supported by a CIHR Project grant (PJT-153311) and a Canada Research Chair in Cellular and Molecular Neurophysiology (CRC-950-231066). R.J.K. is supported by National Institutes of Health (NIH) Project grants (R01 DK113171, R01 DK103185, R01 CA198103 and R01 AG062190). E.S. is supported by the Ministerio de Ciencia, Innovación y Universidades (RTI2018-101838-J-I00) and A.Q. is supported by the European Research Council (ERC-2014-StG-638106), Ministerio de Economía y Competitividad (SAF2017-88108-R) and Agència de Gestió d’Ajuts Universitaris i de Recerca (2017SGR-323). M.C.-M. is supported by the National Institute of Neurological Disorders and Stroke grant (2R01 NS076708-06 NINDS). Support to R.S. was provided by Richard and Edith Strauss Postdoctoral Fellowships in Medicine. We thank the CNAG-CRG for assistance with RNA sequencing; G. S. McKnight for the RPL22-HA plasmid; members of the Sonenberg laboratory, specifically I. Harvey, A. Lafrance, A. Sylvestre, E. Migon and S. Murthy, as well as I. Laplante, H. Hall, M. Anadolu and K. Gamache for support with animals and resources; and S. Tahmasebi for critical reading of the manuscript.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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10.1038/s41586-020-2805-8

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Sharma, V., Sood, R., Khlaifia, A., Eslamizade, M. J., Hung, T. Y., Lou, D., Asgarihafshejani, A., Lalzar, M., Kiniry, S. J., Stokes, M. P., Cohen, N., Nelson, A. J., Abell, K., Possemato, A. P., Gal-Ben-Ari, S., Truong, V. T., Wang, P., Yiannakas, A., Saffarzadeh, F., ... Sonenberg, N. (2020). eIF2α controls memory consolidation via excitatory and somatostatin neurons. Nature, 586(7829), 412-416. https://doi.org/10.1038/s41586-020-2805-8

@article{8d0996c30adb459f9e5140eae24c0e5a,

title = "eIF2α controls memory consolidation via excitatory and somatostatin neurons",

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.",

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

note = "Funding Information: Acknowledgements This study was supported by a Canada{\textquoteright}s International Development Research Centre (IDRC), in partnership with the Azrieli Foundation, the Canadian Institutes of Health Research (CIHR), and the Israel Science Foundation (ISF) to K.R. and N.S. J.-C.L. is supported by a CIHR Project grant (PJT-153311) and a Canada Research Chair in Cellular and Molecular Neurophysiology (CRC-950-231066). R.J.K. is supported by National Institutes of Health (NIH) Project grants (R01 DK113171, R01 DK103185, R01 CA198103 and R01 AG062190). E.S. is supported by the Ministerio de Ciencia, Innovaci{\'o}n y Universidades (RTI2018-101838-J-I00) and A.Q. is supported by the European Research Council (ERC-2014-StG-638106), Ministerio de Econom{\'i}a y Competitividad (SAF2017-88108-R) and Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca (2017SGR-323). M.C.-M. is supported by the National Institute of Neurological Disorders and Stroke grant (2R01 NS076708-06 NINDS). Support to R.S. was provided by Richard and Edith Strauss Postdoctoral Fellowships in Medicine. We thank the CNAG-CRG for assistance with RNA sequencing; G. S. McKnight for the RPL22-HA plasmid; members of the Sonenberg laboratory, specifically I. Harvey, A. Lafrance, A. Sylvestre, E. Migon and S. Murthy, as well as I. Laplante, H. Hall, M. Anadolu and K. Gamache for support with animals and resources; and S. Tahmasebi for critical reading of the manuscript. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = oct,

day = "15",

doi = "10.1038/s41586-020-2805-8",

language = "English",

volume = "586",

pages = "412--416",

journal = "Nature",

issn = "0028-0836",

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Sharma, V, Sood, R, Khlaifia, A, Eslamizade, MJ, Hung, TY, Lou, D, Asgarihafshejani, A, Lalzar, M, Kiniry, SJ, Stokes, MP, Cohen, N, Nelson, AJ, Abell, K, Possemato, AP, Gal-Ben-Ari, S, Truong, VT, Wang, P, Yiannakas, A, Saffarzadeh, F, Cuello, AC, Nader, K, Kaufman, RJ, Costa-Mattioli, M, Baranov, PV, Quintana, A, Sanz, E, Khoutorsky, A, Lacaille, JC, Rosenblum, K & Sonenberg, N 2020, 'eIF2α controls memory consolidation via excitatory and somatostatin neurons', Nature, vol. 586, no. 7829, pp. 412-416. https://doi.org/10.1038/s41586-020-2805-8

TY - JOUR

T1 - eIF2α controls memory consolidation via excitatory and somatostatin neurons

AU - Sharma, Vijendra

AU - Sood, Rapita

AU - Khlaifia, Abdessattar

AU - Eslamizade, Mohammad Javad

AU - Hung, Tzu Yu

AU - Lou, Danning

AU - Asgarihafshejani, Azam

AU - Lalzar, Maya

AU - Kiniry, Stephen J.

AU - Stokes, Matthew P.

AU - Cohen, Noah

AU - Nelson, Alissa J.

AU - Abell, Kathryn

AU - Possemato, Anthony P.

AU - Gal-Ben-Ari, Shunit

AU - Truong, Vinh T.

AU - Wang, Peng

AU - Yiannakas, Adonis

AU - Saffarzadeh, Fatemeh

AU - Cuello, A. Claudio

AU - Nader, Karim

AU - Kaufman, Randal J.

AU - Costa-Mattioli, Mauro

AU - Baranov, Pavel V.

AU - Quintana, Albert

AU - Sanz, Elisenda

AU - Khoutorsky, Arkady

AU - Lacaille, Jean Claude

AU - Rosenblum, Kobi

AU - Sonenberg, Nahum

N1 - Funding Information: Acknowledgements This study was supported by a Canada’s International Development Research Centre (IDRC), in partnership with the Azrieli Foundation, the Canadian Institutes of Health Research (CIHR), and the Israel Science Foundation (ISF) to K.R. and N.S. J.-C.L. is supported by a CIHR Project grant (PJT-153311) and a Canada Research Chair in Cellular and Molecular Neurophysiology (CRC-950-231066). R.J.K. is supported by National Institutes of Health (NIH) Project grants (R01 DK113171, R01 DK103185, R01 CA198103 and R01 AG062190). E.S. is supported by the Ministerio de Ciencia, Innovación y Universidades (RTI2018-101838-J-I00) and A.Q. is supported by the European Research Council (ERC-2014-StG-638106), Ministerio de Economía y Competitividad (SAF2017-88108-R) and Agència de Gestió d’Ajuts Universitaris i de Recerca (2017SGR-323). M.C.-M. is supported by the National Institute of Neurological Disorders and Stroke grant (2R01 NS076708-06 NINDS). Support to R.S. was provided by Richard and Edith Strauss Postdoctoral Fellowships in Medicine. We thank the CNAG-CRG for assistance with RNA sequencing; G. S. McKnight for the RPL22-HA plasmid; members of the Sonenberg laboratory, specifically I. Harvey, A. Lafrance, A. Sylvestre, E. Migon and S. Murthy, as well as I. Laplante, H. Hall, M. Anadolu and K. Gamache for support with animals and resources; and S. Tahmasebi for critical reading of the manuscript. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2020/10/15

Y1 - 2020/10/15

N2 - 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.

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ER -

eIF2α controls memory consolidation via excitatory and somatostatin neurons

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