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.