TRANSGENIC MOUSE MODEL OF THE SLOW-CHANNEL SYNDROME

To investigate the effect of acetylcholine receptor (AChR) mutations o n neuromuscular transmission and to develop a model for the human neur omuscular disease, the slow-channel syndrome, we generated transgenic mice with abnormal AChRs using a delta subunit with a mutation in the ion channel domain. In three transgenic lines, nerve-evoked end-plate currents and spontaneous miniature end-plate currents (MEPCs) had prol onged decay phases and MEPC amplitudes were reduced by 33%. Single ner ve stimuli elicited repetitive compound muscle action potentials in vi vo. Transgenic mice were abnormally sensitive to the neuromuscular blo cker, curare. These observations demonstrate that we can predictably a lter AChR function, synaptic responses, and muscle fiber excitation in vivo by overexpressing subunits containing well-defined mutations. Fu rthermore these data support the hypothesis that the electrophysiologi cal findings in the neuromuscular disorder, the slow-channel syndrome, are due to mutant AChRs. (C) 1996 John Wiley & Sons, Inc.