title: Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions.
abstract: Autoantibodies to the smaller isoform of glutamate decarboxylase (GAD) can be found in patients with type 1 diabetes and a number of neurological disorders, including stiff-person syndrome, cerebellar ataxia and limbic encephalitis. The detection of disease-specific autoantibody epitopes led to the hypothesis that distinct GAD autoantibodies may elicit specific neurological phenotypes. We explored the in vitro/in vivo effects of well-characterized monoclonal GAD antibodies. We found that GAD autoantibodies present in patients with stiff person syndrome (n = 7) and cerebellar ataxia (n = 15) recognized an epitope distinct from that recognized by GAD autoantibodies present in patients with type 1 diabetes mellitus (n = 10) or limbic encephalitis (n = 4). We demonstrated that the administration of a monoclonal GAD antibody representing this epitope specificity; (1) disrupted in vitro the association of GAD with γ-Aminobutyric acid containing synaptic vesicles; (2) depressed the inhibitory synaptic transmission in cerebellar slices with a gradual time course and a lasting suppressive effect; (3) significantly decreased conditioned eyelid responses evoked in mice, with no modification of learning curves in the classical eyeblink-conditioning task; (4) markedly impaired the facilitatory effect exerted by the premotor cortex over the motor cortex in a paired-pulse stimulation paradigm; and (5) induced decreased exploratory behavior and impaired locomotor function in rats. These findings support the specific targeting of GAD by its autoantibodies in the pathogenesis of stiff-person syndrome and cerebellar ataxia. Therapies of these disorders based on selective removal of such GAD antibodies could be envisioned.
authors: Unité d'Etude du Mouvement, FNRS Neurologie, ULB Erasme Brussels, Belgium.
authors: Mario
authors: M
authors: Manto
authors: Neuroscience Research Center INSERM Lyon, France.
authors: Jérôme
authors: J
authors: Honnorat
authors: School of Medicine, University of Washington Seattle, WA, USA.
authors: Christiane S
authors: CS
authors: Hampe
authors: Division of Neurosciences, Pablo de Olavide University Seville, Spain.
authors: Rafael
authors: R
authors: Guerra-Narbona
authors: Division of Neurosciences, Pablo de Olavide University Seville, Spain.
authors: Juan Carlos
authors: JC
authors: López-Ramos
authors: Division of Neurosciences, Pablo de Olavide University Seville, Spain.
authors: José María
authors: JM
authors: Delgado-García
authors: Department of Pharmacology, Nippon Medical School Tokyo, Japan.
authors: Fumihito
authors: F
authors: Saitow
authors: Department of Pharmacology, Nippon Medical School Tokyo, Japan.
authors: Hidenori
authors: H
authors: Suzuki
authors: Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and JST, CREST, Maebashi City Gunma, Japan.
authors: Yuchio
authors: Y
authors: Yanagawa
authors: National Center of Neurology and Psychiatry Tokyo, Japan.
authors: Hidehiro
authors: H
authors: Mizusawa
authors: Department of Medical Education, Tokyo Medical University Tokyo, Japan.
authors: Hiroshi
authors: H
authors: Mitoma
keywords: GABAergic neurotransmission; GAD65; autoantibodies; epitopes; stiff person syndrome