Abstract

Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1–2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.

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Acknowledgements

This work was primarily funded by the Canadian Institute for Health Research (CIHR) and the Ontario Brain Institute (OBI). JE received salary support from the Ontario Mental Health Foundation (OHMF) and RMH holds a Canada Research Chair.

Author information

Affiliations

  1. Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada

    • J Ellegood
    • , C L Laliberté
    • , M C van Eede
    • , R M Henkelman
    •  & J P Lerch
  2. Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada

    • E Anagnostou
  3. Laboratory of Behavioral Neurosciences, National Institute of Mental Health, Bethesda, MD, USA

    • B A Babineau
    •  & J N Crawley
  4. Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, Sacramento, CA, USA

    • J N Crawley
  5. Department of Neurosciences and Cell Biology, UMDNJ—Robert Wood Johnson Medical School, Piscataway, NJ, USA

    • L Lin
    • , M Genestine
    •  & E DiCicco-Bloom
  6. The Brain-Body Institute, McMaster University, Hamilton, ON, Canada

    • J K Y Lai
    •  & J A Foster
  7. Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

    • O Peñagarikano
    •  & D H Geschwind
  8. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada

    • L K Pacey
    •  & D R Hampson
  9. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    • A A Mills
  10. Departments of Medicine and Molecular Genetics, University of Toronto, Toronto, ON, Canada

    • E Tam
    •  & L R Osborne
  11. Departments of Neurology and Neurotherapeutics, Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • M Kouser
    • , F Espinosa-Becerra
    • , Z Xuan
    •  & C M Powell
  12. Child Psychiatry Branch, National Institutes of Mental Health, Bethesda, MD, USA

    • A Raznahan
  13. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA

    • D M Robins
  14. Department of Mental Biology, RIKEN Brain Science Institute, Wako, Japan

    • N Nakai
    • , J Nakatani
    •  & T Takumi
  15. Department of Pharmacology, Vanderbilt Kennedy Center, Vanderbilt Brain Institute, Nashville, TN, USA

    • T M Kerr
    • , C Muller
    • , R D Blakely
    •  & J Veenstra-VanderWeele
  16. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    • R M Henkelman
    •  & J P Lerch

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Competing interests

EA has received consultation fees from Novartis and Seaside therapeutics, and has an unrestricted grant from Sanofi Canada. JV-VW receives research funding from Seaside Therapeutics, Novartis, Roche Pharmaceuticals, Forest, Sunovion and SynapDx and sits on the advisory board for Novartis and Roche Pharmaceuticals. The remaining authors declare no conflict of interest.

Corresponding authors

Correspondence to J Ellegood or J P Lerch.

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DOI

https://doi.org/10.1038/mp.2014.98

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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