TY - JOUR
T1 - Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure
T2 - A novel rat model of sydenham chorea and related neuropsychiatric disorders
AU - Brimberg, Lior
AU - Benhar, Itai
AU - Mascaro-Blanco, Adita
AU - Alvarez, Kathy
AU - Lotan, Dafna
AU - Winter, Christine
AU - Klein, Julia
AU - Moses, Allon E.
AU - Somnier, Finn E.
AU - Leckman, James F.
AU - Swedo, Susan E.
AU - Cunningham, Madeleine W.
AU - Joel, Daphna
N1 - Funding Information: 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).
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
KW - PANDAS
KW - Sydenham chorea (SC)
KW - animal model
KW - autoimmunity
KW - dopamine
KW - streptococcus group A (GAS)
UR - http://www.scopus.com/inward/record.url?scp=84863988844&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/npp.2012.56
DO - https://doi.org/10.1038/npp.2012.56
M3 - مقالة
SN - 0893-133X
VL - 37
SP - 2076
EP - 2087
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 9
ER -