title: Stiff person syndrome associated anti-amphiphysin antibodies reduce GABA associated [Ca(2+)]i rise in embryonic motoneurons.
abstract: Autoantibodies to the synaptic protein amphiphysin play a crucial pathogenic role in paraneoplastic stiff-person syndrome. Impairment of GABAergic inhibition is the presumed pathophysiological mechanism by which these autoantibodies become pathogenic. Here we used calcium imaging on rat embryonic motor neurons to investigate whether antibodies to amphiphysin directly hinder GABAergic signaling. We found that the immunoglobulin G fraction from a patient with stiff-person syndrome, containing high titer antibodies to amphiphysin and inducing stiffness in rats upon passive transfer, reduced GABA-induced calcium influx in embryonic motor neurons. Depletion of the anti-amphiphysin fraction from the patient's IgG by selective affinity chromatography abolished this effect, showing its specificity for amphiphysin. Quantification of the surface expression of the Na(+)/K(+)/2Cl(2-) cotransporter revealed a reduction after incubation with anti-amphiphysin IgG, which is concordant with a lower intracellular chloride concentration and thus impairment of GABA mediated calcium influx. Thus, anti-amphiphysin antibodies exert a direct effect on GABA signaling, which is likely to contribute to the pathogenesis of SPS.
authors.affiliation: Department of Neurology, University of Würzburg, Josef-Schneider-Strasse 11, 97080 Würzburg, Germany. Geis_C@klinik.uni-wuerzburg.de
authors.forename: C
authors.initials: C
authors.lastname: Geis
authors.forename: M
authors.initials: M
authors.lastname: Beck
authors.forename: S
authors.initials: S
authors.lastname: Jablonka
authors.forename: A
authors.initials: A
authors.lastname: Weishaupt
authors.forename: K V
authors.initials: KV
authors.lastname: Toyka
authors.forename: M
authors.initials: M
authors.lastname: Sendtner
authors.forename: C
authors.initials: C
authors.lastname: Sommer
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005260:Female; D018682:GABA Agents / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D013116:Spinal Cord / Q000166:cytology; D018709:Statistics, Nonparametric; D027981:Symporters / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*; D000096922:K Cl- Cotransporters
chemical_list: D000906:Antibodies; D002118:Calcium; D018682:GABA Agents; D009419:Nerve Tissue Proteins; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C075637:amphiphysin