title: New insights into short-term synaptic facilitation at the frog neuromuscular junction.
abstract: Short-term synaptic facilitation occurs during high-frequency stimulation, is known to be dependent on presynaptic calcium ions, and persists for tens of milliseconds after a presynaptic action potential. We have used the frog neuromuscular junction as a model synapse for both experimental and computer simulation studies aimed at testing various mechanistic hypotheses proposed to underlie short-term synaptic facilitation. Building off our recently reported excess-calcium-binding-site model of synaptic vesicle release at the frog neuromuscular junction (Dittrich M, Pattillo JM, King JD, Cho S, Stiles JR, Meriney SD. Biophys J 104: 2751-2763, 2013), we have investigated several mechanisms of short-term facilitation at the frog neuromuscular junction. Our studies place constraints on previously proposed facilitation mechanisms and conclude that the presence of a second class of calcium sensor proteins distinct from synaptotagmin can explain known properties of facilitation observed at the frog neuromuscular junction. We were further able to identify a novel facilitation mechanism, which relied on the persistent binding of calcium-bound synaptotagmin molecules to lipids of the presynaptic membrane. In a real physiological context, both mechanisms identified in our study (and perhaps others) may act simultaneously to cause the experimentally observed facilitation. In summary, using a combination of computer simulations and physiological recordings, we have developed a stochastic computer model of synaptic transmission at the frog neuromuscular junction, which sheds light on the facilitation mechanisms in this model synapse.
authors.affiliation: Biomedical Applications Group, Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, Pennsylvania; Joint Carnegie Mellon-University of Pittsburgh PhD Program in Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania;
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Lauren
authors.initials: L
authors.lastname: Kelly
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Justin
authors.initials: J
authors.lastname: Ingram
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Price
authors.affiliation: Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Meriney
authors.affiliation: Biomedical Applications Group, Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, Pennsylvania; Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania dittrich@psc.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Dittrich
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003198:Computer Simulation; D007700:Kinetics; D008563:Membrane Lipids / Q000378:metabolism; D008839:Microelectrodes; D008959:Models, Neurological; D009469:Neuromuscular Junction / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology; D011894:Rana pipiens; D013269:Stochastic Processes; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D020864:Calcium Channels, N-Type; D002135:Calcium-Binding Proteins; D008563:Membrane Lipids; D002118:Calcium
keywords: MCell; frog neuromuscular junction; short-term synaptic plasticity; stochastic simulation; synaptic vesicle release