Abstract
BackgroundStiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). A pathological role of these antibodies has been suggested by their capacity to inhibit GAD65 enzyme activity and by the observation that rats receiving cerebellar injections of GAD65Ab showed cerebellar motor hyperexcitability. To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78).MethodsRats received three injections of GAD65Ab b96.11 (5 or 7 μg), GAD65Ab b78 (5 or 7 μg), or saline at the level of three cerebellar nuclei. Animals were submitted to neurological evaluation and Morris Water Maze (MWM) test. Cellular internalization of GAD65Ab was analyzed by Flow Cytometry, Fluorescence and Bright Field microscopy.ResultsMonoclonal GAD65Ab induced dose-dependent and epitope-specific effects on motor and cognitive functions. Injections of the higher dose altered motor and spatial procedural behaviors, while the lower dose induced only modest cerebellar motor symptoms and did not affect MWM performances. While b96.11 provoked immediate severe effects, which rapidly decreased, b78 induced moderate but prolonged effects. Both GAD65Ab were taken up by live cells in a dose-dependent manner.ConclusionsOur findings support the hypothesis that epitope-specific GAD65Ab induce cerebellar dysfunction impairing motor and procedural abilities. This is the first demonstration of a critical role of cerebellar nuclei GAD65 enzyme in procedural spatial functions.
Highlights
Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS)
Animals injected with 7 μg of GAD65 antibodies (GAD65Ab) Neurological evaluation Twenty hours after injections, 7-b96.11 animals showed more severely impaired motor behaviors compared to 7sham animals
The motor impairment decreased after the first day so that the 7-b96.11 rats no longer differed from 7-sham animals (Figure 2A)
Summary
Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). We concluded that GAD65Ab interfered with the regulation of brain neurotransmitters and thereby impaired neuronal activity This conclusion was recently confirmed in studies demonstrating that purified IgG from a SPS patient with high GAD65Ab titers induced motor dysfunction in rats [15]. To investigate whether disease-specific GAD65Ab are involved in these clinical distinct phenotypes, we utilized two monoclonal GAD65Ab with well-characterized epitope specificities One of these antibodies inhibited GAD65 enzyme activity and shared an epitope recognized by GAD65Ab present in SPS patients [17]. Our hypothesis that different GAD65Ab induce distinct neurological effects was verified when we injected rat cerebellar nuclei with these monoclonal GAD65Ab. Stiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78)
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