2. Academic Validation
  3. Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome

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

  • Neuron. 2023 Oct 4;111(19):3028-3040.e6. doi: 10.1016/j.neuron.2023.06.017.
Mehdi Hooshmandi 1,  Vijendra Sharma 2,  Carolina Thörn Perez 1,  Rapita Sood 2,  Konstanze Krimbacher 3,  Calvin Wong 1,  Kevin C Lister 1,  Alba Ureña Guzmán 1,  Trevor D Bartley 4,  Cecilia Rocha 5,  Gilles Maussion 5,  Emma Nadler 1,  Patricia Margarita Roque 1,  Ilse Gantois 2,  Jelena Popic 2,  Maxime Lévesque 6,  Randal J Kaufman 7,  Massimo Avoli 6,  Elisenda Sanz 8,  Karim Nader 9,  Randi Jenssen Hagerman 10,  Thomas M Durcan 5,  Mauro Costa-Mattioli 11,  Masha Prager-Khoutorsky 12,  Jean-Claude Lacaille 13,  Veronica Martinez-Cerdeno 4,  Jay R Gibson 14,  Kimberly M Huber 14,  Nahum Sonenberg 15,  Christos G Gkogkas 16,  Arkady Khoutorsky 17
Affiliations

Affiliations

  • 1 Department of Anesthesia and Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montréal, QC, Canada.
  • 2 Department of Biochemistry, McGill University, Montréal, QC, Canada.
  • 3 Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
  • 4 Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children of Northern California, MIND Institute, UC Davis Medical Center, Sacramento, CA, USA.
  • 5 The Neuro's Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, QC, Canada.
  • 6 Montreal Neurological Institute-Hospital, Departments of Neurology & Neurosurgery and of Physiology, McGill University, Montréal, QC, Canada.
  • 7 Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 8 Department of Cell Biology, Physiology and Immunology, and Neuroscience Institute, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 9 Department of Psychology, Faculty of Science, McGill University, Montréal, QC, Canada.
  • 10 MIND Institute and Department of Pediatrics, University of California at Davis Medical Center, Sacramento, CA, USA.
  • 11 Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77098, USA.
  • 12 Department of Physiology, McGill University, Montréal, QC, Canada.
  • 13 Department of Neurosciences, Center for Interdisciplinary Research on Brain and Learning, and Research Group on Neural Signaling and Circuitry, Université de Montréal, Montréal, QC, Canada.
  • 14 University of Texas Southwestern Medical Center at Dallas, Department of Neuroscience, Dallas, TX 75390-9111, USA.
  • 15 Department of Biochemistry, McGill University, Montréal, QC, Canada. Electronic address: nahum.sonenberg@mcgill.ca.
  • 16 Biomedical Research Institute, Foundation for Research and Technology-Hellas, University Campus, 45110 Ioannina, Greece. Electronic address: cgkogkas@bri.forth.gr.
  • 17 Department of Anesthesia and Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montréal, QC, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC, Canada. Electronic address: arkady.khoutorsky@mcgill.ca.
PMID: 37473758 DOI: 10.1016/j.neuron.2023.06.017
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.

Keywords

autism; fragile X syndrome; integrated stress response; mRNA translation.

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