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Mutations causing syndromic autism define an axis of synaptic pathophysiology

Author

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  • Benjamin D. Auerbach

    (Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology)

  • Emily K. Osterweil

    (Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology)

  • Mark F. Bear

    (Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology)

Abstract

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2+/− and Fmr1−/y mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.

Suggested Citation

  • Benjamin D. Auerbach & Emily K. Osterweil & Mark F. Bear, 2011. "Mutations causing syndromic autism define an axis of synaptic pathophysiology," Nature, Nature, vol. 480(7375), pages 63-68, December.
    • Handle: RePEc:nat:nature:v:480:y:2011:i:7375:d:10.1038_nature10658
    DOI: 10.1038/nature10658
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    Cited by:

    1. Hain HS & Connolly JJ & Glessner JT & Elia J & Hakonarson H, 2018. "Toward Individualized Treatments for Neurodevelopmental Disorders Targeting Metabotropic Glutamate Receptor (mGluR) Genes Impacted by Copy Number Variants," Open Access Journal of Neurology & Neurosurgery, Juniper Publishers Inc., vol. 8(2), pages 37-42, August.
    2. Vasiliki Karalis & Franklin Caval-Holme & Helen S. Bateup, 2022. "Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Marco Pagani & Noemi Barsotti & Alice Bertero & Stavros Trakoshis & Laura Ulysse & Andrea Locarno & Ieva Miseviciute & Alessia De Felice & Carola Canella & Kaustubh Supekar & Alberto Galbusera & Vinod, 2021. "mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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