Article | Published:

Mutations causing syndromic autism define an axis of synaptic pathophysiology

Nature volume 480, pages 6368 (01 December 2011) | Download Citation

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.

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Acknowledgements

This work was partly supported by grants from the National Institute of Mental Health (T32 MH-082718 and T32-MH-074249), the National Institute of Child Health and Human Development (2R01HD046943), the Department of Defense (W81XWH-11-1-0252) and The Simons Foundation. We acknowledge A. Heynen for advice and comments, as well as K. Oram, E. Sklar and S. Meagher for technical and administrative assistance. Monoclonal Arc antibody was a gift from P. Worley.

Author information

Affiliations

  1. Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Benjamin D. Auerbach
    • , Emily K. Osterweil
    •  & Mark F. Bear

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Contributions

M.F.B. designed, directed and coordinated the project. B.D.A. designed and performed electrophysiological recordings and behaviour tests. E.K.O. designed and performed biochemistry experiments.

Competing interests

M.F.B. has a financial interest in Seaside Therapeutics, Inc.

Corresponding author

Correspondence to Mark F. Bear.

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DOI

https://doi.org/10.1038/nature10658

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