AUTHOR=Manto Mario , Honnorat Jérôme , Hampe Christiane S. , Guerra-Narbona Rafael , López-Ramos Juan Carlos , Delgado-García José María , Saitow Fumihito , Suzuki Hidenori , Yanagawa Yuchio , Mizusawa Hidehiro , Mitoma Hiroshi 

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

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=9

YEAR=2015

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2015.00078

DOI=10.3389/fnbeh.2015.00078

ISSN=1662-5153

ABSTRACT=<p>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 <italic>in vitro/in vivo</italic> effects of well-characterized monoclonal GAD antibodies. We found that GAD autoantibodies present in patients with stiff person syndrome (<italic>n</italic> = 7) and cerebellar ataxia (<italic>n</italic> = 15) recognized an epitope distinct from that recognized by GAD autoantibodies present in patients with type 1 diabetes mellitus (<italic>n</italic> = 10) or limbic encephalitis (<italic>n</italic> = 4). We demonstrated that the administration of a monoclonal GAD antibody representing this epitope specificity; (1) disrupted <italic>in vitro</italic> 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.</p>