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Abstract

We have generated a new mouse model for congenital myasthenic syndromes by inserting the missense mutation L221F into the ? subunit of the acetylcholine receptor by homologous recombination. This mutation has been identified in man to cause a mild form of slow−channel congenital myasthenic syndrome with variable penetrance. In our mouse model we observe as in human patients prolonged endplate currents. The summation of endplate potentials may account for a depolarization block at increasing stimulus frequencies, moderate reduced muscle strength and tetanic fade. Calcium and intracellular vesicle accumulation as well as junctional fold loss and organelle degeneration underlying a typical endplate myopathy, were identified. Moreover, a remodelling of neuromuscular junctions occurs in a muscle−dependent pattern expressing variable phenotypic effects. Altogether, this mouse model provides new insight into the pathophysiology of congenital myasthenia and serves as a new tool for deciphering signalling pathways induced by excitotoxicity at peripheral synapses. Key words: Neuromuscular Junction, Slow Channel Congenital Myasthenic Syndrome, Acetylcholine Receptor, mouse model, homologous recombination