Computational Modeling of Neuromoscular Junction and Evaluation of A Novel Treatment For Neuromuscular Disease

The structure and organization of transmitter release sites is known to be of importance to synapse function. We combine MCell diffusion-reaction computer simulations of a realistic nerve terminal with physiology to advance our understanding of terminal release site organization. We developed healthy and diseased frog and mouse neuromuscular synapse models. We evaluated the effects of varying the spatial distribution of calcium channels and synaptic vesicles in transmission release, studied sub-active zone distribution and function of calcium-activated potassium (BK) channels, predicted changes in action potential shape and its effects on transmitter release. These models are compared and constrained by physiological recordings.

We used our control MCell model (validated by its ability to predict physiology) as a starting point for modeling the current treatments for the neuromuscular disease Lambert-Eaton Myasthenic Syndrome (LEMS). We modeled: A) the current treatment for LEMS, DAP (a potassium channel blocker), B) a newly developed drug (GV-58) that is a calcium channel gating modifier, and C) a combination of the two drugs. We evaluated the model-predicted effects on transmitter release of using different concentration combinations of each drug for future pre-clinical testing.