Cells in the nervous system communicate at specialized regions called synapses. When a nerve fires, calcium ions enter synapses from the surrounding extracellular fluid and cause neurotransmitter molecules to be released into the synaptic cleft between the communicating cells. However, the sequence of molecular events leading from calcium entry to transmitter release remains unknown. To better understand this important process, this research will combine laboratory experiments and large-scale computer simulations to build detailed 3-D models of calcium-triggered neurotransmitter release at the synapse between a nerve and muscle cell in the frog. In many respects, the frog synapse is quite similar to many mammalian synapses (including human), and yet it presents unique opportunities for combined laboratory and computational studies. This makes it an ideal choice for creation of highly realistic and accurate models. Using these models, hypotheses will be developed and tested to explain how synapses use calcium to trigger neurotransmitter release, and how repeated nerve firing changes release, as occurs at all synapses as they respond to changing behavioral conditions. Development of realistic 3-D computer models also presents unique opportunities for transformational training and education. Undergraduate, graduate, and postdoctoral trainees will participate directly in these studies, and high quality animations of the models will be adapted for use in the classroom. The project co-directors (S. Meriney, Univ. of Pittsburgh, and J. Stiles, Carnegie Mellon Univ.) and faculty colleagues will use the new teaching material at the University of Pittsburgh, the Pittsburgh Supercomputing Center, and Carnegie Mellon University, in undergraduate and graduate Neuroscience, Biology, and Computational Biology courses, a multi-institutional summer institute (www.ccbb.pitt.edu/bbsi), workshops, and web-based tutorials (www.mcell.psc.edu/tutorials/tlist.htm). New teaching material will also be featured in the CMIST program, an undergraduate and K-12 outreach program at the National Resource for Biomedical Supercomputing, directed by Dr. Stiles (www.nrbsc.org/cmist).
