Tortuosity and anomalous diffusion in the neuromuscular junction.

The signal transfer from nerve to muscle occurs by diffusion across the neuromuscular junction. The continuum level analysis of diffusion processes is based on the diffusion equation, which in one dimension is partial differential c/partial differential t=D(partial differential(2)c/partial differential x(2)) , where c is the molecular concentration and D is the diffusivity. However, in confined systems such as the neuromuscular junction, the diffusion equation may not be valid, and even if valid the value of D may be altered by the confinement. In this paper, Monte Carlo simulations are used to probe diffusion at the molecular level in a realistic model of a neuromuscular junction. The results show that diffusion is anomalous (i.e., not described by the diffusion equation) for time scales less than approximately 0.01 s, which is the time scale relevant for signaling processes in the synapse. At longer time scales, the diffusion is normal (i.e., described by the diffusion equation), but with a value of D that is reduced by a factor of approximately 5 times compared to the value for diffusion in open space. As the width of the synaptic cleft decreases, these effects become even more pronounced. The physical basis of these results is described in terms of the structure of the neuromuscular junction.