1. Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome
- Author
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Hooshmandi, Mehdi, Sharma, Vijendra, Thörn Perez, Carolina, Sood, Rapita, Krimbacher, Konstanze, Wong, Calvin, Lister, Kevin C, Ureña Guzmán, Alba, Bartley, Trevor D, Rocha, Cecilia, Maussion, Gilles, Nadler, Emma, Roque, Patricia Margarita, Gantois, Ilse, Popic, Jelena, Lévesque, Maxime, Kaufman, Randal J, Avoli, Massimo, Sanz, Elisenda, Nader, Karim, Hagerman, Randi Jenssen, Durcan, Thomas M, Costa-Mattioli, Mauro, Prager-Khoutorsky, Masha, Lacaille, Jean-Claude, Martinez-Cerdeno, Veronica, Gibson, Jay R, Huber, Kimberly M, Sonenberg, Nahum, Gkogkas, Christos G, and Khoutorsky, Arkady
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Autism ,Behavioral and Social Science ,Fragile X Syndrome ,Pediatric ,Rare Diseases ,Intellectual and Developmental Disabilities (IDD) ,Mental Health ,Genetics ,Brain Disorders ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Animals ,Mice ,Autistic Disorder ,Fragile X Mental Retardation Protein ,Autism Spectrum Disorder ,Neurons ,Phenotype ,Mice ,Knockout ,Disease Models ,Animal ,autism ,fragile X syndrome ,integrated stress response ,mRNA translation ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - 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.
- Published
- 2023