Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome

Mehdi Hooshmandi; Vijendra Sharma; Carolina Thörn Perez; Rapita Sood; Konstanze Krimbacher; Calvin Wong; Kevin C. Lister; Alba Ureña Guzmán; Trevor D. Bartley; Cecilia Rocha; Gilles Maussion; Emma Nadler; Patricia Margarita Roque; Ilse Gantois; Jelena Popic; Maxime Lévesque; Randal J. Kaufman; Massimo Avoli; Elisenda Sanz; Karim Nader; Randi Jenssen Hagerman; Thomas M. Durcan; Mauro Costa-Mattioli; Masha Prager-Khoutorsky; Jean Claude Lacaille; Veronica Martinez-Cerdeno; Jay R. Gibson; Kimberly M. Huber; Nahum Sonenberg; Christos G. Gkogkas; Arkady Khoutorsky

doi:10.1016/j.neuron.2023.06.017

Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome

Mehdi Hooshmandi, Vijendra Sharma, Carolina Thörn Perez, Rapita Sood, Konstanze Krimbacher, Calvin Wong, Kevin C. Lister, Alba Ureña Guzmán, Trevor D. Bartley, Cecilia Rocha, Gilles Maussion, Emma Nadler, Patricia Margarita Roque, Ilse Gantois, Jelena Popic, Maxime Lévesque, Randal J. Kaufman, Massimo Avoli, Elisenda Sanz, Karim NaderRandi Jenssen Hagerman, Thomas M. Durcan, Mauro Costa-Mattioli, Masha Prager-Khoutorsky, Jean Claude Lacaille, Veronica Martinez-Cerdeno, Jay R. Gibson, Kimberly M. Huber, Nahum Sonenberg, Christos G. Gkogkas, Arkady Khoutorsky

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Abstract

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1^−/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1^−/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.

Original language	English (US)
Pages (from-to)	3028-3040.e6
Journal	Neuron
Volume	111
Issue number	19
DOIs	https://doi.org/10.1016/j.neuron.2023.06.017
State	Published - Oct 4 2023

Keywords

autism
fragile X syndrome
integrated stress response
mRNA translation

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2023.06.017

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Hooshmandi, M., Sharma, V., Thörn Perez, C., Sood, R., Krimbacher, K., Wong, C., Lister, K. C., Ureña Guzmán, A., Bartley, T. D., Rocha, C., Maussion, G., Nadler, E., Roque, P. M., Gantois, I., Popic, J., Lévesque, M., Kaufman, R. J., Avoli, M., Sanz, E., ... Khoutorsky, A. (2023). Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome. Neuron, 111(19), 3028-3040.e6. https://doi.org/10.1016/j.neuron.2023.06.017

Hooshmandi, M, Sharma, V, Thörn Perez, C, Sood, R, Krimbacher, K, Wong, C, Lister, KC, Ureña Guzmán, A, Bartley, TD, Rocha, C, Maussion, G, Nadler, E, Roque, PM, Gantois, I, Popic, J, Lévesque, M, Kaufman, RJ, Avoli, M, Sanz, E, Nader, K, Hagerman, RJ, Durcan, TM, Costa-Mattioli, M, Prager-Khoutorsky, M, Lacaille, JC, Martinez-Cerdeno, V, Gibson, JR , Huber, KM, Sonenberg, N, Gkogkas, CG & Khoutorsky, A 2023, 'Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome', Neuron, vol. 111, no. 19, pp. 3028-3040.e6. https://doi.org/10.1016/j.neuron.2023.06.017

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title = "Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome",

abstract = "Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1−/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1−/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.",

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author = "Mehdi Hooshmandi and Vijendra Sharma and {Th{\"o}rn Perez}, Carolina and Rapita Sood and Konstanze Krimbacher and Calvin Wong and Lister, {Kevin C.} and {Ure{\~n}a Guzm{\'a}n}, Alba and Bartley, {Trevor D.} and Cecilia Rocha and Gilles Maussion and Emma Nadler and Roque, {Patricia Margarita} and Ilse Gantois and Jelena Popic and Maxime L{\'e}vesque and Kaufman, {Randal J.} and Massimo Avoli and Elisenda Sanz and Karim Nader and Hagerman, {Randi Jenssen} and Durcan, {Thomas M.} and Mauro Costa-Mattioli and Masha Prager-Khoutorsky and Lacaille, {Jean Claude} and Veronica Martinez-Cerdeno and Gibson, {Jay R.} and Huber, {Kimberly M.} and Nahum Sonenberg and Gkogkas, {Christos G.} and Arkady Khoutorsky",

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AU - Hooshmandi, Mehdi

AU - Sharma, Vijendra

AU - Thörn Perez, Carolina

AU - Sood, Rapita

AU - Krimbacher, Konstanze

AU - Wong, Calvin

AU - Lister, Kevin C.

AU - Ureña Guzmán, Alba

AU - Bartley, Trevor D.

AU - Rocha, Cecilia

AU - Maussion, Gilles

AU - Nadler, Emma

AU - Roque, Patricia Margarita

AU - Gantois, Ilse

AU - Popic, Jelena

AU - Lévesque, Maxime

AU - Kaufman, Randal J.

AU - Avoli, Massimo

AU - Sanz, Elisenda

AU - Nader, Karim

AU - Hagerman, Randi Jenssen

AU - Durcan, Thomas M.

AU - Costa-Mattioli, Mauro

AU - Prager-Khoutorsky, Masha

AU - Lacaille, Jean Claude

AU - Martinez-Cerdeno, Veronica

AU - Gibson, Jay R.

AU - Huber, Kimberly M.

AU - Sonenberg, Nahum

AU - Gkogkas, Christos G.

AU - Khoutorsky, Arkady

PY - 2023/10/4

Y1 - 2023/10/4

N2 - Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1−/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1−/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.

AB - Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1−/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1−/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.

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KW - integrated stress response

KW - mRNA translation

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JO - Neuron

JF - Neuron

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ER -

Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome

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