SYNAPTOTAGMIN CAN CAUSE AN IMMUNE-MEDIATED MODEL OF LAMBERT-EATON MYASTHENIC SYNDROME IN RATS

The possible antigenicity of synaptotagmin, a synaptic vesicle protein acting as a cooperative calcium (Ca2+) receptor in exocytosis, was te sted to determine whether it is involved in the induction of Lambert-E aton myasthenic syndrome in which antibodies against voltage-dependent Ca2+ channels or related molecules play a pathogenic role. Repeated i njections to Lewis rats with peptides of synaptotagmin residues 20 thr ough 53 or 1 through 30 that are presumably exposed at the nerve termi nal surface during exocytosis induced corresponding antipeptide antibo dies; on immunoblots, antibodies recognized synaptotagmin that was exp ressed in the clonal cells. Electrophysiologically, the peptide (resid ues 20-53)-immunized rats showed (1) reduced acetylcholine quantal con tent of end-plate potential, (2) an increase in quantal content at hig h extracellular Ca2+ concentration, and (3) early facilitation followe d by less marked depression of end-plate potential amplitude at a teta nic rate of repetitive nerve stimulation Findings We similar to those in human Lambert-Eaton myasthenic syndrome and passively transferred L ambert-Eaton myasthenic syndrome in mice, and thus suggest that antibo dy to a synaptotagmin-voltage-dependent Ca2+ channel complex may be in volved in the pathogenesis of Lambert-Eaton myasthenic syndrome. The p eptide (residues 1-30)-immunized tars showed no electrophysiological a bnormality.