Selective stabilization of muscle innervation during development: a mathematical model.

The biochemical model presented concerns a critical step of the development of skeletal muscle innervation. After invasion of the muscle by exploratory motor axons, several nerve terminals converge from different motoneurons onto each muscle fibre at a single endplate. During the following weeks the redundant innervation disappears: a single nerve ending per muscle fibre becomes stabilized. The model is based on the assumption that the numbers of motoneurons and of muscle fibres remain constant during this evolution and that the selective stabilization of the adult connectivity results from the competition of the active nerve terminals for a postsynaptic retrograde factor mu. At the peak of the multiple innervation, the synthesis of mu by the muscle fiber stops, possibly as a consequence of muscle electrical and/or mechanical activity. The stock of mu becomes limited; a retrograde trans-synaptic diffusion of mu from the muscle to the nerve endings takes place. Within each nerve ending, mu enters into a chemical autocatalytic reaction which results in the production of a presynaptic stabilization factor s. The nerve impulses reaching the nerve terminal initiate this reaction. Any given nerve terminal become stabilized when the concentration of s reaches a threshold value. The mathematical analysis of the model shows that there exists a unique solution which is physically acceptable. Its application and computer simulation predict that only one nerve terminal becomes stabilized per muscle fibre. The model accounts for the experimental observations that the reduction in size of the motor units is not necessarily accompanied by a reduction in the variability of their size. The model also accounts for the acceleration or delay in regression which follows modifications of the chronic activity of the nerve endings and for the variability of the pattern of innervation observed in isogenic organisms. Plausible biochemical hypotheses concerning the factors engaged in the "selective stabilization" of the nerve-endings are discussed.