title: Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats.
abstract: BACKGROUND
  Stiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). A pathological role of these antibodies has been suggested by their capacity to inhibit GAD65 enzyme activity and by the observation that rats receiving cerebellar injections of GAD65Ab showed cerebellar motor hyperexcitability. To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78).
  
  
  METHODS
  Rats received three injections of GAD65Ab b96.11 (5 or 7 μg), GAD65Ab b78 (5 or 7 μg), or saline at the level of three cerebellar nuclei. Animals were submitted to neurological evaluation and Morris Water Maze (MWM) test. Cellular internalization of GAD65Ab was analyzed by Flow Cytometry, Fluorescence and Bright Field microscopy.
  
  
  RESULTS
  Monoclonal GAD65Ab induced dose-dependent and epitope-specific effects on motor and cognitive functions. Injections of the higher dose altered motor and spatial procedural behaviors, while the lower dose induced only modest cerebellar motor symptoms and did not affect MWM performances. While b96.11 provoked immediate severe effects, which rapidly decreased, b78 induced moderate but prolonged effects. Both GAD65Ab were taken up by live cells in a dose-dependent manner.
  
  
  CONCLUSIONS
  Our findings support the hypothesis that epitope-specific GAD65Ab induce cerebellar dysfunction impairing motor and procedural abilities. This is the first demonstration of a critical role of cerebellar nuclei GAD65 enzyme in procedural spatial functions.
authors.affiliation: University of Washington, School of Medicine, SLU S-276, Seattle, WA 98109, USA. champe@u.washington.edu
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
authors.forename: Laura
authors.initials: L
authors.lastname: Petrosini
authors.forename: Paola
authors.initials: P
authors.lastname: De Bartolo
authors.forename: Paola
authors.initials: P
authors.lastname: Caporali
authors.forename: Debora
authors.initials: D
authors.lastname: Cutuli
authors.forename: Daniela
authors.initials: D
authors.lastname: Laricchiuta
authors.forename: Francesca
authors.initials: F
authors.lastname: Foti
authors.forename: Jared R
authors.initials: JR
authors.lastname: Radtke
authors.forename: Veronika
authors.initials: V
authors.lastname: Vidova
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.forename: Mario
authors.initials: M
authors.lastname: Manto
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D001323:Autoantibodies; D001522:Behavior, Animal / Q000187:drug effects*; D002460:Cell Line; D003071:Cognition / Q000187:drug effects*; D000939:Epitopes / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology*; D008297:Male; D009048:Motor Skills / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D020033:Protein Isoforms / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D016750:Stiff-Person Syndrome / Q000276:immunology / Q000503:physiopathology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; D020033:Protein Isoforms; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2