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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.

Author information

1
Unité d'Etude du Mouvement, FNRS Neurologie, ULB Erasme Brussels, Belgium.
2
Neuroscience Research Center INSERM Lyon, France.
3
School of Medicine, University of Washington Seattle, WA, USA.
4
Division of Neurosciences, Pablo de Olavide University Seville, Spain.
5
Department of Pharmacology, Nippon Medical School Tokyo, Japan.
6
Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and JST, CREST, Maebashi City Gunma, Japan.
7
National Center of Neurology and Psychiatry Tokyo, Japan.
8
Department of Medical Education, Tokyo Medical University Tokyo, Japan.

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.

KEYWORDS:

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

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