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.

DOI: 10.3389/fnbeh.2015.00078

Extracted Key Phrases

11 Figures and Tables

0100200201520162017
Citations per Year

96 Citations

Semantic Scholar estimates that this publication has 96 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@inproceedings{Manto2015DiseasespecificMA, title={Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions}, author={Mario Manto and J{\'e}r{\^o}me Honnorat and Christiane S. Hampe and Rafael Guerra-Narbona and Juan Carlos L{\'o}pez-Ramos and Jos{\'e} Mar{\'i}a Delgado-Garc{\'i}a and Fumihito Saitow and Hidenori Suzuki and Yuchio Yanagawa and Hidehiro Mizusawa and Hiroshi Mitoma}, booktitle={Front. Behav. Neurosci.}, year={2015} }