Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness,
spasms and anxiety occur in paraneoplastic
stiff person syndrome with
autoantibodies against the intracellular synaptic
protein amphiphysin. Here we show that intrathecal application of purified anti-
amphiphysin immunoglobulin G antibodies induces
stiff person syndrome-like symptoms in rats, including stiffness and
muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-
amphiphysin immunoglobulin G was internalized into neurons by an
epitope-specific mechanism and colocalized in vivo with presynaptic vesicular
proteins, as shown by stimulation emission depletion microscopy. Neurons from
amphiphysin deficient mice that did not internalize the
immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-
amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic
protein AP180 and by defective loading of
FM 1-43, a styryl
dye used to label cell membranes. Incubation of cultured neurons with anti-
amphiphysin immunoglobulin G reduced basal and stimulated release of γ-
aminobutyric acid substantially more than that of
glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with
antibodies against
amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of
stiff person syndrome at the molecular level and show that
autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key
protein by disturbing vesicular endocytosis.