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

Hooshmandi, M.; Sharma, V.; Perez, C. T.; Sood, R.; Simbriger, K.; Wong, C.; Lister, K. C.; Guzman, A. U.; Bartley, T. D.; Rocha, C.; Maussion, G.; Nadler, E.; Roque, P. M.; Gantois, I.; Popic, J.; Levesque, M.; Kaufman, R. J.; Avoli, M.; Sanz, E.; Nader, K.; Hagerman, R. J.; Durcan, T. M.; Costa-Mattioli, M.; Lacaille, J.-C.; Martinez-Cerdeno, V.; Gibson, J. R.; Huber, K.; Sonenberg, N.; Gkogkas, C. G.; Khoutorsky, A.

doi:10.1101/2023.04.24.538123

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bioRxiv · 10.1101/2023.04.24.538123

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

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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, eIF2 phosphorylation (p-eIF2), 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-eIF2 is mediated via activation of the mTORC1. Genetic reduction of p-eIF2 only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, genetic restoration of p-eIF2 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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Hooshmandi, M., Sharma, V., Perez, C. T., Sood, R., Simbriger, K., Wong, C., Lister, K. C., Guzman, A. U., Bartley, T. D., Rocha, C., Maussion, G., Nadler, E., Roque, P. M., Gantois, I., Popic, J., Levesque, M., Kaufman, R. J., Avoli, M., Sanz, E., Nader, K., Hagerman, R. J., Durcan, T. M., Costa-Mattioli, M., Lacaille, J.-C., Martinez-Cerdeno, V., Gibson, J. R., Huber, K., Sonenberg, N., Gkogkas, C. G., Khoutorsky, A.. 2023-04-24. Excitatory neuron-specific suppression of the integrated stress response pathway contributes to autism-related phenotypes in a mouse model of fragile X syndrome. https://doi.org/10.1101/2023.04.24.538123

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