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Autism-specific maternal autoantibodies produce behavioral abnormalities in an endogenous antigen-driven mouse model of autism

Molecular Psychiatry (2018) | Download Citation

Abstract

Immune dysregulation has been noted consistently in individuals with autism spectrum disorder (ASD) and their families, including the presence of autoantibodies reactive to fetal brain proteins in nearly a quarter of mothers of children with ASD versus <1% in mothers of typically developing children. Our lab recently identified the peptide epitope sequences on seven antigenic proteins targeted by these maternal autoantibodies. Through immunization with these peptide epitopes, we have successfully created an endogenous, antigen-driven mouse model that ensures a constant exposure to the salient autoantibodies throughout gestation in C57BL/6J mice. This exposure more naturally mimics what is observed in mothers of children with ASD. Male and female offspring were tested using a comprehensive sequence of behavioral assays, as well as measures of health and development highly relevant to ASD. We found that MAR-ASD male and female offspring had significant alterations in development and social interactions during dyadic play. Although 3-chambered social approach was not significantly different, fewer social interactions with an estrous female were noted in the adult male MAR-ASD animals, as well as reduced vocalizations emitted in response to social cues with robust repetitive self-grooming behaviors relative to saline treated controls. The generation of MAR-ASD-specific epitope autoantibodies in female mice prior to breeding created a model that demonstrates for the first time that ASD-specific antigen-induced maternal autoantibodies produced alterations in a constellation of ASD-relevant behaviors.

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Acknowledgements

We would like to give a special thank you to Luke Heuer and Krista Haapanen for their contributions to this project. This study was funded by the NIEHS Center for Children’s Environmental Health and Environmental Protection Agency (EPA) grants (2P01ES011269-11, 83543201, respectively), the NIEHS-funded CHARGE study (R01ES015359), and the NICHD funded IDDRC 054 (U54HD079125), the Hearst Foundation, and The Hartwell Foundation.

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Affiliations

  1. Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA

    • Karen L. Jones
    • , Elizabeth Edmiston
    •  & Judy Van de Water
  2. MIND Institute, University of California, Davis, CA, USA

    • Karen L. Jones
    • , Jill L. Silverman
    • , Jacqueline N. Crawley
    •  & Judy Van de Water
  3. Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA, USA

    • Michael C. Pride
    • , Mu Yang
    • , Jill L. Silverman
    •  & Jacqueline N. Crawley
  4. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA

    • Mu Yang

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Conflict of interest

J.V.d.W. and E.E. have a patent application involving the MAR-ASD peptides described herein; all the remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Judy Van de Water.

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https://doi.org/10.1038/s41380-018-0126-1