title: Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats.
abstract: Stiff person syndrome (SPS) is an autoimmune CNS disorder characterized by muscle rigidity, spasms and anxiety. The majority of patients have high-titer autoantibodies (ab) against glutamate decarboxylase (GAD65). A pathogenic role of SPS-associated IgG with ab against GAD65 has been shown for anxiety-like behavior but not for the core motor signs. We repetitively injected the purified IgG fraction of an SPS patient with severe motor impairment but without anxious comorbidity containing high titers of anti-GAD65 ab (SPS-IgG) into the lateral ventricle (i.c.v.) or intrathecally (i.th.) at the spinal level in experimental rats. We analyzed the effects on motor and anxiety-like behavior. Non-SPS human IgG fractions served as controls. Animals injected i.c.v. with SPS-IgG showed stiffness-like behavior with impaired walking ability and reduced grip strength of the upper limbs as well as postural and sensorimotor dysfunction. Testing for anxiety-like behavior revealed no significant differences between SPS and control IgG-treated rats. IgG deposits were found only in rats treated with SPS-IgG and were localized predominantly in CNS structures involved in motor control including globus pallidus, internal capsule, striatum and anterior thalamus. Double immunofluorescence staining revealed that predominantly GABAergic interneurons were positive for i.c.v. injected SPS-IgG. Rats injected i.th. with SPS-IgG did not present obvious motor symptoms and had a normal synaptic transmission at the spinal level. We conclude that SPS-like motor dysfunction can be induced in rats by passive transfer of IgG from an SPS-patient with high titer of anti-GAD65 ab. GABAergic dysfunction in supraspinal motor pathways rather than in the spinal cord may lead to motor deficits observed in the rats contrasting observations made in SPS with amphiphysin antibodies.
authors.affiliation: Department of Neurology, University of Würzburg, Josef-Schneider Strasse 11, 97080 Würzburg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Hansen
authors.forename: Benedikt
authors.initials: B
authors.lastname: Grünewald
authors.forename: Andreas
authors.initials: A
authors.lastname: Weishaupt
authors.forename: Maria Nandini
authors.initials: MN
authors.lastname: Colaço
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.forename: Christian
authors.initials: C
authors.lastname: Geis
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology; D001323:Autoantibodies / Q000302:isolation & purification / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004409:Dyskinesia, Drug-Induced / Q000473:pathology / Q000503:physiopathology*; D055724:Electrophysiological Phenomena; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006181:H-Reflex / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000302:isolation & purification / Q000494:pharmacology*; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009048:Motor Skills / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D016750:Stiff-Person Syndrome / Q000276:immunology* / Q000473:pathology
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2