SLOW-CHANNEL TRANSGENIC MICE - A MODEL OF POSTSYNAPTIC ORGANELLAR DEGENERATION AT THE NEUROMUSCULAR-JUNCTION

The slow-channel congenital myasthenic syndrome (SCCMS) is a dominantl y inherited disorder of neuromuscular transmission characterized by de layed closure of the skeletal muscle acetylcholine receptor (AChR) ion channel and degeneration of the neuromuscular junction. The identific ation of a series of AChR subunit mutations in the SCCMS supports the hypothesis that the altered kinetics of the endplate currents in this disease are attributable to inherited abnormalities of the AChR. To in vestigate the role of these mutant AChR subunits in the development of the synaptic degeneration seen in the SCCMS, we have studied the prop erties of the AChR mutation, epsilon L269F, found in a family with SCC MS, using both in vitro and in vivo expression systems. The mutation c auses a sixfold increase in the open time of AChRs expressed in vitro, similar to the phenotype of other reported mutants. Transgenic mice e xpressing this mutant develop a syndrome that is highly reminiscent of the SCCMS. Mice have fatigability of limb muscles, electrophysiologic al evidence of slow AChR ion channels, and defective neuromuscular tra nsmission. Pathologically, the motor end-plates show focal accumulatio n of calcium and striking ultrastructural changes, including enlargeme nt and degeneration of the subsynaptic mitochondria and nuclei. These findings dearly demonstrate the role of this mutation in the spectrum of abnormalities associated with the SCCMS and point to the subsynapti c organelles as principal targets in this disease. These transgenic mi ce provide a useful model for the study of excitotoxic synaptic degene ration.