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

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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References

  1. APA. Diagnostic and statistical manual of mental disorders: DSM-V. 5th. Arlington, VA: American Psychiatric Association; 2013.

    Google Scholar 

  2. Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018;67(SS-6):1-23. https://doi.org/10.15585/mmwr.ss6706a1.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68:1095–102.

    PubMed  PubMed Central  Google Scholar 

  4. Gronborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatr. 2013;167:947–53.

    PubMed  PubMed Central  Google Scholar 

  5. Kim YS, Leventhal BL. Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol Psychiatry. 2015;77:66–74.

    CAS  PubMed  Google Scholar 

  6. Meltzer A, Van de Water J. The role of the immune system in autism spectrum disorder. Neuropsychopharmacology. 2017;42:284–98.

    CAS  PubMed  Google Scholar 

  7. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, et al. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology. 2007;29:226–31.

    PubMed  PubMed Central  Google Scholar 

  8. Singer HS, Morris CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol. 2008;194:165–72.

    CAS  PubMed  Google Scholar 

  9. Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Mol Psychiatry. 2013;18:1171–7.

    CAS  PubMed  Google Scholar 

  10. Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA, et al. Maternal antibrain antibodies in autism. Brain Behav Immun. 2007;21:351–7.

    CAS  PubMed  Google Scholar 

  11. Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav. 2012;62:263–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Garty BZ, Ludomirsky A, Danon YL, Peter JB, Douglas SD. Placental transfer of immunoglobulin G subclasses. Clin Diagn Lab Immunol. 1994;1:667–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Saunders NR, Liddelow SA, Dziegielewska KM. Barrier mechanisms in the developing brain. Front Pharmacol. 2012;3:46.

    PubMed  PubMed Central  Google Scholar 

  14. Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-reactive antibodies and disease. Annu Rev Immunol. 2013;31:345–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Edmiston E, Ashwood P, Van de Water J. Autoimmunity, autoantibodies, and autism spectrum disorder. Biol Psychiatry. 2017;81:383–90.

    CAS  PubMed  Google Scholar 

  16. Braunschweig D, Duncanson P, Boyce R, Hansen R, Ashwood P, Pessah IN, et al. Behavioral correlates of maternal antibody status among children with autism. J Autism Dev Disord. 2012;42:1435–45.

    PubMed  PubMed Central  Google Scholar 

  17. Croen LA, Braunschweig D, Haapanen L, Yoshida CK, Fireman B, Grether JK, et al. Maternal mid-pregnancy autoantibodies to fetal brain protein: the early markers for autism study. Biol Psychiatry. 2008;64:583–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW, Pletnikov M. Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: a pregnant dam mouse model. J Neuroimmunol. 2009;211:39–48.

    CAS  PubMed  Google Scholar 

  19. Kadam SD, French BM, Kim ST, Morris-Berry CM, Zimmerman AW, Blue ME, et al. Altered postnatal cell proliferation in brains of mouse pups prenatally exposed to IgG from mothers of children with autistic disorder. J Exp Neurosci. 2013;7:93–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Braunschweig D, Golub MS, Koenig CM, Qi L, Pessah IN, Van de Water J, et al. Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model. J Neuroimmunol. 2012;252:56–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Martinez-Cerdeno V, Camacho J, Fox E, Miller E, Ariza J, Kienzle D, et al. Prenatal exposure to autism-specific maternal autoantibodies alters proliferation of cortical neural precursor cells, enlarges brain, and increases neuronal size in adult animals. Cereb Cortex. 2016;26:374–83.

    PubMed  Google Scholar 

  22. Ariza J, Hurtado J, Rogers H, Ikeda R, Dill M, Steward C, et al. Maternal autoimmune antibodies alter the dendritic arbor and spine numbers in the infragranular layers of the cortex. PLoS ONE. 2017;12:e0183443.

    PubMed  PubMed Central  Google Scholar 

  23. Camacho J, Jones KL, Miller E, Ariza J, Noctor S, Van de Water J, et al. Embryonic intraventricular exposure to autism-specific maternal autoantibodies produces alterations in autistic-like stereotypical behaviors in offspring mice. Behav Brain Res. 2014;266:46–51.

    PubMed  PubMed Central  Google Scholar 

  24. Brimberg L, Mader S, Jeganathan V, Berlin R, Coleman TR, Gregersen PK, et al. Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice. Mol Psychiatry. 2016;21:1663–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav Immun. 2008;22:806–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry. 2013;3:e278.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Nordahl CW, Braunschweig D, Iosif AM, Lee A, Rogers S, Ashwood P, et al. Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav Immun. 2013;30:61–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P, et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl Psychiatry. 2013;3:e277.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lopes MH, Hajj GN, Muras AG, Mancini GL, Castro RM, Ribeiro KC, et al. Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J Neurosci. 2005;25:11330–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Edmiston E, Jones KL, Vu T, Ashwood P, Van de Water J. Identification of the antigenic epitopes of maternal autoantibodies in autism spectrum disorders. Brain Behav Immun. 2017;69:399–407.

    PubMed  PubMed Central  Google Scholar 

  31. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10.

    CAS  PubMed  Google Scholar 

  32. Yang M, Bozdagi O, Scattoni ML, Wohr M, Roullet FI, Katz AM, et al. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci. 2012;32:6525–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Nadler JJ, Moy SS, Dold G, Trang D, Simmons N, Perez A, et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 2004;3:303–14.

    CAS  PubMed  Google Scholar 

  34. McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav. 2008;7:152–63.

    CAS  PubMed  Google Scholar 

  35. Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci. 2010;11:490–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Brielmaier J, Matteson PG, Silverman JL, Senerth JM, Kelly S, Genestine M, et al. Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice. PLoS ONE. 2012;7:e40914.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chadman KK, Gong S, Scattoni ML, Boltuck SE, Gandhy SU, Heintz N, et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res. 2008;1:147–58.

    PubMed  PubMed Central  Google Scholar 

  38. Ey E, Yang M, Katz AM, Woldeyohannes L, Silverman JL, Leblond CS, et al. Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4. Genes Brain Behav. 2012;11:928–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Flannery BM, Silverman JL, Bruun DA, Puhger KR, McCoy MR, Hammock BD, et al. Behavioral assessment of NIH Swiss mice acutely intoxicated with tetramethylenedisulfotetramine. Neurotoxicol Teratol. 2015;47:36–45.

    CAS  PubMed  Google Scholar 

  40. Portmann T, Yang M, Mao R, Panagiotakos G, Ellegood J, Dolen G, et al. Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Rep. 2014;7:1077–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Scattoni ML, Gandhy SU, Ricceri L, Crawley JN. Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism. PLoS ONE. 2008;3:e3067.

    PubMed  PubMed Central  Google Scholar 

  42. Wohr M, Silverman JL, Scattoni ML, Turner SM, Harris MJ, Saxena R, et al. Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2. Behav Brain Res. 2013;251:50–64.

    CAS  PubMed  Google Scholar 

  43. Bales KL, Solomon M, Jacob S, Crawley JN, Silverman JL, Larke RH, et al. Long-term exposure to intranasal oxytocin in a mouse autism model. Transl Psychiatry. 2014;4:e480.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Dhamne SC, Silverman JL, Super CE, Lammers SHT, Hameed MQ, Modi ME, et al. Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism. Mol Autism. 2017;8:26.

    PubMed  PubMed Central  Google Scholar 

  45. Kazdoba TM, Hagerman RJ, Zolkowska D, Rogawski MA, Crawley JN. Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism. Psychopharmacology. 2016;233:309–23.

    CAS  PubMed  Google Scholar 

  46. Kazdoba TM, Leach PT, Crawley JN. Behavioral phenotypes of genetic mouse models of autism. Genes Brain Behav. 2016;15:7–26.

    CAS  PubMed  Google Scholar 

  47. Scattoni ML, Ricceri L, Crawley JN. Unusual repertoire of vocalizations in adult BTBR T+tf/J mice during three types of social encounters. Genes Brain Behav. 2011;10:44–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Silverman JL, Pride MC, Hayes JE, Puhger KR, Butler-Struben HM, Baker S, et al. GABAB receptor agonist R-Baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism. Neuropsychopharmacology. 2015;40:2228–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang M, Mahrt EJ, Lewis F, Foley G, Portmann T, Dolmetsch RE, et al. 16p11.2 deletion syndrome mice display sensory and ultrasonic vocalization deficits during social interactions. Autism Res. 2015;8:507–21.

    PubMed  PubMed Central  Google Scholar 

  50. Yang M, Silverman JL, Crawley JN. Automated three-chambered social approach task for mice. Current protocols in neuroscience / editorial board, Jacqueline N Crawley [et al.] 2011; Chapter 8: Unit 8 26.

  51. Beversdorf DQ, Consortium MAS. Phenotyping, etiological factors, and biomarkers: toward precision medicine in autism spectrum disorders. J Dev Behav Pediatr. 2016;37:659–73.

    PubMed  PubMed Central  Google Scholar 

  52. Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R. Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology. 2009;204:361–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Heuer L, Braunschweig D, Ashwood P, Van de Water J, Campbell DB. Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. Transl Psychiatry. 2011;1:e48.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Eagleson KL, Xie Z, Levitt P. The pleiotropic MET receptor network: circuit development and the neural-medical interface of autism. Biol Psychiatry. 2017;81:424–33.

    CAS  PubMed  Google Scholar 

  55. Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA. 2006;103:16834–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Campbell DB, Li C, Sutcliffe JS, Persico AM, Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 2008;1:158–68.

    Google Scholar 

  57. Jackson PB, Boccuto L, Skinner C, Collins JS, Neri G, Gurrieri F, et al. Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder. Autism Res. 2009;2:232–6.

    PubMed  Google Scholar 

  58. Thanseem I, Nakamura K, Miyachi T, Toyota T, Yamada S, Tsujii M, et al. Further evidence for the role of MET in autism susceptibility. Neurosci Res. 2010;68:137–41.

    CAS  PubMed  Google Scholar 

  59. Krakowiak P, Walker CK, Tancredi D, Hertz-Picciotto I, Van de Water J. Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Res. 2017;10:89–98.

    PubMed  Google Scholar 

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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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Correspondence to Judy Van de Water.

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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.

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Jones, K.L., Pride, M.C., Edmiston, E. et al. Autism-specific maternal autoantibodies produce behavioral abnormalities in an endogenous antigen-driven mouse model of autism. Mol Psychiatry 25, 2994–3009 (2020). https://doi.org/10.1038/s41380-018-0126-1

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