Abstract
BackgroundTo investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects.MethodsPurified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods.ResultsIntra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity.ConclusionsThese results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab.
Highlights
To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects
These results suggested that a patient with cerebellar ataxia (Ab CA) and a SPS patient (Ab SPS) exerted different effects upon GAD65 activity and cellular membranes turnover
Trains of transcranial direct current stimulation (tDCS) unraveled a spreading of high-level excitability areas of the motor cortex contralaterally to the administration of Ab CA
Summary
To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. Sommer et al reported that injections of rats with the IgG fraction of an SPS patient with anti-amphiphysin antibodies resulted in a dose-dependent stiffness with spasms mimicking those of human SPS [16,17] Taken together, these results strongly support that SPS is directly caused by the effect of antibodies on spinal cord neurons, both in antiamphiphysin and GAD65-Ab positive cases. GAD65-Ab acting upon cerebellar pathways might induce lesions reaching an irreversible stage, with neuronal destruction and cerebellar atrophy in a chronic situation This hypothesis is supported by the recent publication of an autopsy of a patient with both CA and SPS showing only Purkinje cells loss and no abnormalities in the spinal cord [19]
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