TY - JOUR
T1 - Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats
AU - Lotan, Dafna
AU - Benhar, Itai
AU - Alvarez, Kathy
AU - Mascaro-Blanco, Adita
AU - Brimberg, Lior
AU - Frenkel, Dan
AU - Cunningham, Madeleine W.
AU - Joel, Daphna
N1 - Funding Information:
M.W.C. is Chief Scientific Officer with a financial interest in Moleculera Labs which provides diagnostic testing of children with autoimmune neuropsychiatric and movement disorders. Moleculera Labs resides at the University of Oklahoma Health Sciences Center and Presbyterian Health Foundation Research Park in Oklahoma City, OK. M.W.C. has research funding from National Institutes of Health (Grant No. HL56267), from the National Institutes of Mental Health (Bench to Bedside Grant) and from Oklahoma Center for the Advancement of Science and Technology. D.J. has research funding from the Israel Science Foundation (Grant No. 341/07). All other authors assert that none has any commercial or financial involvements that might present an appearance of a conflict of interest in connection with the submitted manuscript.
Funding Information:
We thank Dr. Dan Frenkel and his laboratory members, Hilit Levy-Barazany, Dorit Trudler and Dorit Farfara (Department of Neurobiology, Tel-Aviv University, Israel) for their assistance in the immunohistochemical analyses. This research was supported by the Israel Science Foundation (Grant No. 341/07 ) to D.J. and National Institutes of Health Grant HL56267 , Bench to Bedside Grant from the National Institutes of Mental Health, and the Oklahoma Center for the Advancement of Science and Technology Grant to M.W.C.
PY - 2014/5
Y1 - 2014/5
N2 - Group A β-hemolytic streptococcal (GAS) infection is associated with a spectrum of neuropsychiatric disorders. The leading hypothesis regarding this association proposes that a GAS infection induces the production of auto-antibodies, which cross-react with neuronal determinants in the brain through the process of molecular mimicry. We have recently shown that exposure of rats to GAS antigen leads to the production of anti-neuronal antibodies concomitant with the development of behavioral alterations. The present study tested the causal role of the antibodies by assessing the behavior of naïve rats following passive transfer of purified antibodies from GAS-exposed rats. Immunoglobulin G (IgG) purified from the sera of GAS-exposed rats was infused directly into the striatum of naïve rats over a 21-day period. Their behavior in the induced-grooming, marble burying, food manipulation and beam walking assays was compared to that of naïve rats infused with IgG purified from adjuvant-exposed rats as well as of naïve rats. The pattern of in vivo antibody deposition in rat brain was evaluated using immunofluorescence and colocalization. Infusion of IgG from GAS-exposed rats to naïve rats led to behavioral and motor alterations partially mimicking those seen in GAS-exposed rats. IgG from GAS-exposed rats reacted with D1 and D2 dopamine receptors and 5HT-2A and 5HT-2C serotonin receptors in vitro. In vivo, IgG deposits in the striatum of infused rats colocalized with specific brain proteins such as dopamine receptors, the serotonin transporter and other neuronal proteins. Our results demonstrate the potential pathogenic role of autoantibodies produced following exposure to GAS in the induction of behavioral and motor alterations, and support a causal role for autoantibodies in GAS-related neuropsychiatric disorders.
AB - Group A β-hemolytic streptococcal (GAS) infection is associated with a spectrum of neuropsychiatric disorders. The leading hypothesis regarding this association proposes that a GAS infection induces the production of auto-antibodies, which cross-react with neuronal determinants in the brain through the process of molecular mimicry. We have recently shown that exposure of rats to GAS antigen leads to the production of anti-neuronal antibodies concomitant with the development of behavioral alterations. The present study tested the causal role of the antibodies by assessing the behavior of naïve rats following passive transfer of purified antibodies from GAS-exposed rats. Immunoglobulin G (IgG) purified from the sera of GAS-exposed rats was infused directly into the striatum of naïve rats over a 21-day period. Their behavior in the induced-grooming, marble burying, food manipulation and beam walking assays was compared to that of naïve rats infused with IgG purified from adjuvant-exposed rats as well as of naïve rats. The pattern of in vivo antibody deposition in rat brain was evaluated using immunofluorescence and colocalization. Infusion of IgG from GAS-exposed rats to naïve rats led to behavioral and motor alterations partially mimicking those seen in GAS-exposed rats. IgG from GAS-exposed rats reacted with D1 and D2 dopamine receptors and 5HT-2A and 5HT-2C serotonin receptors in vitro. In vivo, IgG deposits in the striatum of infused rats colocalized with specific brain proteins such as dopamine receptors, the serotonin transporter and other neuronal proteins. Our results demonstrate the potential pathogenic role of autoantibodies produced following exposure to GAS in the induction of behavioral and motor alterations, and support a causal role for autoantibodies in GAS-related neuropsychiatric disorders.
KW - Animal model
KW - Dopamine
KW - Pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS)
KW - Serotonin
KW - Streptococcus group A (GAS)
KW - Sydenham's chorea (SC)
UR - http://www.scopus.com/inward/record.url?scp=84898540917&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2014.02.009
DO - 10.1016/j.bbi.2014.02.009
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C2 - 24561489
AN - SCOPUS:84898540917
SN - 0889-1591
VL - 38
SP - 249
EP - 262
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -