title: Human stiff-person syndrome IgG induces anxious behavior in rats.
abstract: BACKGROUND
  Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear.
  
  
  RESULTS
  We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats.
  
  
  CONCLUSIONS
  The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany. Geis_C@klinik.uni-wuerzburg.de
authors.forename: Christian
authors.initials: C
authors.lastname: Geis
authors.forename: Andreas
authors.initials: A
authors.lastname: Weishaupt
authors.forename: Benedikt
authors.initials: B
authors.lastname: Grünewald
authors.forename: Thomas
authors.initials: T
authors.lastname: Wultsch
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Manfred
authors.initials: M
authors.lastname: Gerlach
authors.forename: Ron
authors.initials: R
authors.lastname: Dirkx
authors.forename: Michele
authors.initials: M
authors.lastname: Solimena
authors.forename: Daniela
authors.initials: D
authors.lastname: Perani
authors.forename: Manfred
authors.initials: M
authors.lastname: Heckmann
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
mesh_terms: D000328:Adult; D000679:Amygdala / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects*; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D005260:Female; D005442:Flumazenil / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000276:immunology; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D049268:Positron-Emission Tomography; D051381:Rats; D016750:Stiff-Person Syndrome / Q000378:metabolism* / Q000523:psychology; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D007074:Immunoglobulin G; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2