Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

Argel Aguilar-Valles; Nabila Haji; Danilo De Gregorio; Edna Matta-Camacho; Mohammad J. Eslamizade; Jelena Popic; Vijendra Sharma; Ruifeng Cao; Christoph Rummel; Arnaud Tanti; Shane Wiebe; Nicolas Nuñez; Stefano Comai; Robert Nadon; Giamal Luheshi; Naguib Mechawar; Gustavo Turecki; Jean Claude Lacaille; Gabriella Gobbi; Nahum Sonenberg

doi:10.1038/s41467-018-04883-5

Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

Argel Aguilar-Valles, Nabila Haji, Danilo De Gregorio, Edna Matta-Camacho, Mohammad J. Eslamizade, Jelena Popic, Vijendra Sharma, Ruifeng Cao, Christoph Rummel, Arnaud Tanti, Shane Wiebe, Nicolas Nuñez, Stefano Comai, Robert Nadon, Giamal Luheshi, Naguib Mechawar, Gustavo Turecki, Jean Claude Lacaille, Gabriella Gobbi, Nahum Sonenberg

Biomedical Sciences

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

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Abstract

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2 ^-/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety-and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses.

Original language	English (US)
Article number	2459
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04883-5
State	Published - Dec 1 2018

Bibliographical note

Funding Information:
We thank David E. Szymkowski (Xencor, Inc., Monrovia, CA) for the generous donation of XPro1595; Jeremy Graff (Eli Lilly, Indianapolis, IN) for the generous donation of cercosporamide, and Annie Sylvestre, Annik Lafrance, Isabelle Harvey, Isabel Laplante, Luca Posa, Ada Posner, Grace Ling, Joshua Byer, Doreen Marks and Hansen Tsui for technical assistance. We thank Prof. Joseph Rochford for his help in data analysis. A.A.-V. was recipient of FRQS (Fond Recherche Québec-Santé) and CIHR (Canadian Institutes for Health Research) postdoctoral fellowships. D.D.G. was a recipient of FQRNT (Fonds de Recherche du Québec – Nature et technologies) postdoctoral fellowship. N.N. was supported by the Quebec Network on Suicide, Mood Disorders and Related Disorders. J.-C.L. is the recipient of the Canada Research Chair in Cellular and Molecular Neurophysiology. This work was supported by a CIHR Foundation grant to N.S. (FND-148423), a CIHR operating grant to J.-C.L. (MOP-125985), and a Fonds de la Recherche du Québec - Santé (FRQS) Group grant (Groupe de Recherche sur le Système Nerveux Central [GRSNC]) to J.-C.L.

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© 2018 The Author(s).

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018502

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Aguilar-Valles, A., Haji, N., De Gregorio, D., Matta-Camacho, E., Eslamizade, M. J., Popic, J., Sharma, V., Cao, R., Rummel, C., Tanti, A., Wiebe, S., Nuñez, N., Comai, S., Nadon, R., Luheshi, G., Mechawar, N., Turecki, G., Lacaille, J. C., Gobbi, G., & Sonenberg, N. (2018). Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E. Nature communications, 9(1), [2459]. https://doi.org/10.1038/s41467-018-04883-5

Aguilar-Valles, A, Haji, N, De Gregorio, D, Matta-Camacho, E, Eslamizade, MJ, Popic, J, Sharma, V, Cao, R, Rummel, C, Tanti, A, Wiebe, S, Nuñez, N, Comai, S, Nadon, R, Luheshi, G, Mechawar, N, Turecki, G, Lacaille, JC, Gobbi, G & Sonenberg, N 2018, 'Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E', Nature communications, vol. 9, no. 1, 2459. https://doi.org/10.1038/s41467-018-04883-5

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title = "Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E",

abstract = "Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2 -/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety-and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses.",

author = "Argel Aguilar-Valles and Nabila Haji and {De Gregorio}, Danilo and Edna Matta-Camacho and Eslamizade, {Mohammad J.} and Jelena Popic and Vijendra Sharma and Ruifeng Cao and Christoph Rummel and Arnaud Tanti and Shane Wiebe and Nicolas Nu{\~n}ez and Stefano Comai and Robert Nadon and Giamal Luheshi and Naguib Mechawar and Gustavo Turecki and Lacaille, {Jean Claude} and Gabriella Gobbi and Nahum Sonenberg",

note = "Funding Information: We thank David E. Szymkowski (Xencor, Inc., Monrovia, CA) for the generous donation of XPro1595; Jeremy Graff (Eli Lilly, Indianapolis, IN) for the generous donation of cercosporamide, and Annie Sylvestre, Annik Lafrance, Isabelle Harvey, Isabel Laplante, Luca Posa, Ada Posner, Grace Ling, Joshua Byer, Doreen Marks and Hansen Tsui for technical assistance. We thank Prof. Joseph Rochford for his help in data analysis. A.A.-V. was recipient of FRQS (Fond Recherche Qu{\'e}bec-Sant{\'e}) and CIHR (Canadian Institutes for Health Research) postdoctoral fellowships. D.D.G. was a recipient of FQRNT (Fonds de Recherche du Qu{\'e}bec – Nature et technologies) postdoctoral fellowship. N.N. was supported by the Quebec Network on Suicide, Mood Disorders and Related Disorders. J.-C.L. is the recipient of the Canada Research Chair in Cellular and Molecular Neurophysiology. This work was supported by a CIHR Foundation grant to N.S. (FND-148423), a CIHR operating grant to J.-C.L. (MOP-125985), and a Fonds de la Recherche du Qu{\'e}bec - Sant{\'e} (FRQS) Group grant (Groupe de Recherche sur le Syst{\`e}me Nerveux Central [GRSNC]) to J.-C.L. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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doi = "10.1038/s41467-018-04883-5",

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T1 - Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

AU - Aguilar-Valles, Argel

AU - Haji, Nabila

AU - De Gregorio, Danilo

AU - Matta-Camacho, Edna

AU - Eslamizade, Mohammad J.

AU - Popic, Jelena

AU - Sharma, Vijendra

AU - Cao, Ruifeng

AU - Rummel, Christoph

AU - Tanti, Arnaud

AU - Wiebe, Shane

AU - Nuñez, Nicolas

AU - Comai, Stefano

AU - Nadon, Robert

AU - Luheshi, Giamal

AU - Mechawar, Naguib

AU - Turecki, Gustavo

AU - Lacaille, Jean Claude

AU - Gobbi, Gabriella

AU - Sonenberg, Nahum

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N2 - Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2 -/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety-and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses.

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Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

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