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Front Behav Neurosci. 2015 Mar 27;9:78. doi: 10.3389/fnbeh.2015.00078. eCollection 2015.

Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions.

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Unité d'Etude du Mouvement, FNRS Neurologie, ULB Erasme Brussels, Belgium.
Neuroscience Research Center INSERM Lyon, France.
School of Medicine, University of Washington Seattle, WA, USA.
Division of Neurosciences, Pablo de Olavide University Seville, Spain.
Department of Pharmacology, Nippon Medical School Tokyo, Japan.
Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and JST, CREST, Maebashi City Gunma, Japan.
National Center of Neurology and Psychiatry Tokyo, Japan.
Department of Medical Education, Tokyo Medical University Tokyo, Japan.


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.


GABAergic neurotransmission; GAD65; autoantibodies; epitopes; stiff person syndrome

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