Calcium Dynamics in Exocytosis and Synaptic Facilitation

New Jersey Institute Of Technology, Newark NJ

Investigators

Abstract

This project will use a combination of analytical, computational and experimental techniques to gain a deeper understanding of the synaptic release of neurotransmitter, termed exocytosis. It will address such open questions as the precise sequence of steps linking calcium ion entry into the cell to exocytosis, the involvement of individual calcium channels in neurotransmitter release, and the mechanisms of transient calcium-dependent facilitation of synaptic response, presumably caused by the accumulation of calcium at the exocytosis site. More specifically, this project will focus on the impact of intrinsic and externally applied calcium binding substances termed calcium buffers on exocytosis and its facilitation, using mathematical and computational modeling of calcium diffusion inside the cell. The importance of calcium buffers stems from the fact that they absorb more than 95% of calcium ions entering the cell; further, the sensitivity of exocytosis and facilitation to applied buffers provides one of the most widely used methods to probe the intrinsic calcium sensitivity of these processes. The first specific goal of this project is to reveal the effect of such buffers on the cooperativity of individual calcium channels in triggering exocytosis of a single vesicle, and to re-examine the so-called calcium current cooperativity measurements that probe the arrangement of channels at the release site. The second specific goal is to examine the proposed non-local property of the buffer saturation phenomenon, whereby the transient whole-terminal depletion of free buffer by calcium influx through one group of channels may cause subsequent opening of the same or another group of channels to produce a greater calcium elevation. Further, the competition between two calcium buffers in their regulation of intracellular calcium will be explored. Finally, this project will examine the possible functional consequences of synaptic facilitation for the dynamics of neural circuits. Neurotransmitter release at chemical synapses (exocytosis) represents the most common form of communication between two neurons in any biological neural system, including the mammalian cortex, and the knowledge of its mechanisms is indispensable for a full understanding of inter-neuronal interactions and neural information processing. Further, the regulation of neurotransmitter release and binding to receptors represents the main pharmacological treatment method in many neurological and psychiatric pathologies. The importance of this project stems from its combined use of advanced computational tools and experimental physiological techniques in gaining deeper understanding of the neurotransmitter release process, known to depend on the action of calcium ions inside the cell. This project will focus on the precise sequence of exocytosis steps starting with the entry of calcium through cell membrane calcium channels, their subsequent accumulation and binding to intracellular calcium-binding substances, and ending with the calcium-triggered release of neurotransmitter-filled vesicles into the synapse. This investigation should also lead to a better understanding of other vital physiological processes controlled by calcium ions, from gene expression regulation to muscle cell contraction in the heart. Further, this project will involve the use and further development of a publicly accessible computational modeling tool called CalC ("Calcium Calculator"), designed by the Principle Investigator for the modeling of three-dimensional calcium ion diffusion inside the cell (http://www.calciumcalculator.org). This will contribute to the infrastructure for computational modeling in the biological sciences and will also serve as a useful training instrument in the fields of cell neurophysiology and biophysics. All modeling results obtained in the course of this project will be made publicly available through the on-line model database, ensuring the most rapid and effective dissemination of the obtained results. Finally, this project will create student training opportunities in the highly interdisciplinary fields of mathematical biology, biophysics and computational neuroscience, including the training of students from under-represented ethnic groups, since this work will be conducted in an institution with one of the most ethnically diverse student bodies in the country (NJIT).