Thomas M. Bartol
Speaker of Workshop 2
Will talk about: How to build a synapse from molecules, membranes, and Monte Carlo methods
Tom Bartol received his Ph.D. in Cellular and Molecular Neurobiology in 1992 from Cornell University in the laboratory of Mika Salpeter. His Ph.D. work with Mika, her husband Ed Salpeter, and colleague Bruce Land involved studies of synaptic structure and function at the neuromuscular junction using two-electrode voltage-clamp and computer simulations -- the first Monte Carlo simulations of miniature end-plate currents at the NMJ were performed at this time. The seed for MCell, a general Monte Carlo simulator of cellular reaction diffusion systems, was planted and began to grow, especially after Joel Stiles joined Mika's lab as a post-doc in 1990. Tom joined Terry Sejnowski's Computational Neurobiology Laboratory as a post-doc in 1992. In Terry's lab, Tom sought to take what he had learned about synaptic transmission at the NMJ and apply it to the study of synapses of the central nervous system resulting in the release of the first version of MCell in 1996. Over the years Tom's research and collaborations on the spatiotemporal dynamics of neuronal cell signaling pathways have been a major driving factor behind his continuing efforts to improve MCell.
Biochemical signaling pathways are integral to the information storage, transmission, and transformation roles played by neurons in the nervous system. Far from behaving as well-mixed bags of biochemical soup, the intra- and inter-cellular environments in and around neurons are highly organized reaction-diffusion systems, with some subcellular specializations consisting of just a few copies each of the various molecular species they contain. For example, glutamtergic synapses at dendritic spines in area CA1 hippocampal pyramidal cells contain perhaps 100 AMPA receptors, 10 NMDA receptors, around 200 CaMKII holoenzymes, and 5 free Ca++ ions in the spine head at rest. Much experimental data has been gathered about the neuronal signaling pathways involved in processes such as synaptic plasticity, especially recently, thanks to new molecular probes and advanced imaging techniques. Yet, fitting these observations into a clear and consistent picture that is more than just a cartoon but rather can provide biophysically accurate predictions of function has proven difficult due to the complexity of the interacting pieces and their relationships. MCell is a Monte Carlo simulator designed for the purpose of simulating exactly these sorts of cell signaling systems. Here, I will present how biophysically accurate computational experiments performed on the cell signaling pathways involved in synaptic transmission can be a powerful way to help formulate and test new hypotheses in conjunction with bench experiments. I will introduce fundamental concepts of cell signaling processes in the organized and compact spaces of synapses. We have gained some surprising new insights into the workings of the synapse through building realistic models of neurotransmission with MCell.