Generalized molecular defects of the neuromuscular junction in skeletal muscle of the wobbler mutant mouse.

Available models of motorneuron disease that occur naturally in animals provide a useful approach to study human motorneuron disease. The wobbler mutant mouse displays a hereditary lower motorneuron disease which leads to progressive partial denervation of skeletal muscle and, at the same time, axonal regeneration with attempted reinnervation. In order to determine the consequences of these processes at the neuromuscular level, we undertook a study of key molecular components of the neuromuscular junction in wobbler mice. Increased levels of acetylcholine-receptor (AChR) and neural cell adhesion molecule (N-CAM) in wobbler muscle, together with an intense axon sprouting, suggest a complex denervation-reinnervation phenomenon. Furthermore, the appearance of ectopic clusters of AChR, spatially related with regrowth of axons, suggests ectopic formation of new synaptic areas, while, at the same time, some old synaptic sites fail to be reinnervated. Finally, 90% of wobbler neuromuscular contacts present a reduced acetylcholinesterase activity and a lack of N-CAM, which suggests a generalized defect of the mutant neuromuscular junction. These observed abnormalities may well be the consequence of a specific motorneuron defect.