Original Article | Published:

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

Neuropsychopharmacology volume 37, pages 20762087 (2012) | Download Citation

Abstract

Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders.

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Acknowledgements

We thank Professor D Michaelson (Department of Neurobiology, Tel-Aviv University, Israel) for helpful discussions and immunohistochemical assistance, Dr Christine Kirvan (California State University at Sacramento, CA) for helpful discussions, and Reinhard Sohr (at the University Medicine Charité, Berlin, Germany) for the biochemistry analysis. We express gratitude to all of the parents who donated funds to our project. This work was funded in part by the Israel Science Foundation Grant 341/07 to DJ and ADAMS Super Center for Brain Studies at Tel Aviv University to DJ; in part by NIH-R37HL35280 (NIH MERIT AWARD) and NIH-R01HL56267 to MWC; in part by the Oklahoma Center for the Advancement of Science and Technology (OCAST) to MWC; in part by the PANDAS Research Fund at the Oklahoma University Foundation to MWC; in part by the NIMH Bench to Bedside grant to JFL, MWC, and SES; and in part by NIH-5R25MH077823 and Grifols (formerly Talecris Biotherapeutics) to JFL. The human specimens from Yale University were collected as part of the NIH-funded grants to JFL (NIH-R01MH061940, NIH-P01MH049351, and NIH-K05MH076273).

Author information

Author notes

    • Madeleine W Cunningham
    •  & Daphna Joel

    MWC and DJ are co-senior authors.

Affiliations

  1. School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel

    • Lior Brimberg
    • , Dafna Lotan
    •  & Daphna Joel
  2. Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel

    • Itai Benhar
  3. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    • Adita Mascaro-Blanco
    • , Kathy Alvarez
    •  & Madeleine W Cunningham
  4. Department of Psychiatry, Technical University Dresden, Dresden, Germany

    • Christine Winter
  5. Department of Psychiatry, Charité University Medicine Berlin, Berlin, Germany

    • Christine Winter
    •  & Julia Klein
  6. Department of Clinical Microbiology and Infectious Diseases, Hadassah University Hospital, Jerusalem, Israel

    • Allon E Moses
  7. Department of Clinical Biochemistry and Immunology, Statens Serum Institute, Copenhagen, Denmark

    • Finn E Somnier
  8. Yale Child Study Center, Departments of Pediatrics and Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    • James F Leckman
  9. Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD, USA

    • Susan E Swedo

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Competing interests

The authors declare that over the past 3 years, JFL has received compensation from NIH-5R25MH077823 and Grifols (formerly Talecris Biotherapeutics) for the conduct of an IVIG randomized clinical trial in children with Pediatric Neuropsychiatric Disorders Associated with Streptoccocal Infections (PANDAS) as part of an NIMH Bench to Bedside grant to JFL, SES, and MWC; and MWC has received compensation from NIH-R37HL35280 (NIH MERIT AWARD), NIH-R01HL56267, and Moleculera Labs, a company for diagnostics including Sydenham chorea and PANDAS.

Corresponding author

Correspondence to Madeleine W Cunningham.

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DOI

https://doi.org/10.1038/npp.2012.56

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)

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