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Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice

Molecular Psychiatry volume 21, pages 1663–1671 (2016)Cite this article

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Abstract

Autism spectrum disorder (ASD) occurs in 1 in 68 births, preferentially affecting males. It encompasses a group of neurodevelopmental abnormalities characterized by impaired social interaction and communication, stereotypic behaviors and motor dysfunction. Although recent advances implicate maternal brain-reactive antibodies in a causative role in ASD, a definitive assessment of their pathogenic potential requires cloning of such antibodies. Here, we describe the isolation and characterization of monoclonal brain-reactive antibodies from blood of women with brain-reactive serology and a child with ASD. We further demonstrate that male but not female mice exposed in utero to the C6 monoclonal antibody, binding to contactin-associated protein-like 2 (Caspr2), display abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as impairments in sociability, flexible learning and repetitive behavior. Anti-Caspr2 antibodies are frequent in women with brain-reactive serology and a child with ASD. Together these studies provide a methodology for obtaining monclonal brain-reactive antibodies from blood B cells, demonstrate that ASD can result from in utero exposure to maternal brain-reactive antibodies of single specificity and point toward the exciting possibility of prognostic and protective strategies.

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Acknowledgements

We thank the Simons Foundation and Elena Kowalsky at the Feinstein Institute for help obtaining blood samples. We also thank Dr Kevin J Tracey for helpful comments. The research was funded by the Department of Defense (AR130137), NIH (R43 MH106195), and The Nancy Lurie Marks Foundation and The Simons Foundation. LB is a recipient of a Brain and Behavior NARSAD Young Investigator Foundation Grant. We thank Dr. Czeslawa Kowal for her assistance in perfusing embryos.

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  1. L Brimberg and S Mader: Co-first authors.

Authors and Affiliations

  1. Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    L Brimberg, S Mader, V Jeganathan, T R Coleman & B Diamond

  2. Laboratory of Functional Neuroanatomy, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    R Berlin & B T Volpe

  3. Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    P K Gregersen

  4. Laboratory of Immune & Neural Networks, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    P T Huerta

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Brimberg, L., Mader, S., Jeganathan, V. et al. Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice. Mol Psychiatry 21, 1663–1671 (2016). https://doi.org/10.1038/mp.2016.165

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