EAGER: Structure-Function Relationships at the Motor Nerve Terminal Active Zone

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Decades of work comparing neuromuscular synapses in both crayfish and lizards have led to a general acceptance of the dogma that the structure of a synapse has little impact on its function. As a result, the study of structure-function relationships at synapses has been stymied, and, instead, investigators have focused mechanistic studies on the identification of differences in molecules and events associated with transmitter release and calcium signaling. In this project, a comparative study of neuromuscular junctions from frog and mouse skeletal muscle will be carried out using new techniques and a predictive computational model developed in the project collaborators' laboratories. These animal models offer several important advantages. The neuromuscular junctions of frogs and mice serve similar roles (as opposed to previously studied synapses that served different roles in the crayfish and lizard animal models) and yet, have distinct differences in their physiological properties and pre-synaptic structure and organization. The driving hypothesis is that key physiological features of neuromuscular synapses are determined by the structural arrangement of basic building blocks of synaptic structure. This work will offer opportunities for training undergraduate, graduate, and post-graduate students, and high school teachers. Because this is a collaborative project, all trainees will have the unique opportunity to learn both experimental and computational approaches. Importantly, it is expected that the MCell computational model will provide an example of unprecedented scale and realism for the illustration of nerve terminal structure and function with the potential to literally transform a student's grasp of difficult biochemical concepts in space and time. This model will also illustrate and teach the use of Monte Carlo simulations, sophisticated visualization and animation software, and a variety of statistical analysis methods.