Motor endplate disease affects neuromuscular junction maturation

Postnatal formation of the neuromuscular synapse requires complex interactions among nerve terminal, muscle fibres and terminal Schwann cells. In motor endplate disease (med) mice, neuromuscular transmission is severely impaired without alteration of axonal conduction and a lethal paralytic phenotype occurs during the postnatal period. The med phenotype appears at a crucial stage of the neuromuscular junction development, corresponding to the increase in terminal Schwann cell number, the elimination of the multiple innervations and the pre- and postsynaptic maturation. Here we investigated the early cellular and molecular consequences of the med mutation on neuromuscular junction development. We observed that cellular defects preceded overt clinical phenotype. The first detectable cellular effect of the mutation at the onset of the clinical phenotype was a drastic reduction in the number of terminal Schwann cells, in part due to an increase in glial apoptosis, and a delayed maturation of motor endplates. We also showed that, in terminally ill animals, mono-innervation was not achieved, synaptic vesicles had accumulated in the presynaptic compartment and, finally, the size of motor endplates was reduced. All together, our findings suggested that the clinical weakness in these mutant mice was likely to be related to postnatal structural abnormalities of the neuromuscular junction maturation.