Date of Award

Summer 2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Micro and Nanoscale Systems

First Advisor

Robert Szlavik

Abstract

The rise of terrorism has created an interest in better ways to detect when humans are exposed to neurotoxins, especially nerve gases developed for military use, most of which are acetylcholinesterase inhibitors. Many current methods of detection are based on mass spectrometry, a method that is cumbersome and not particularly robust when used as an early warning method. The detection of acetylcholinesterase inhibitors would benefit from a combined model of the processes occurring in the neuromuscular junction between the presynaptic action potential and the motor end-plate action potential that includes the kinetics of acetylcholine and acetylcholinesterase in the synaptic cleft. The ability to simulate the impact of different amounts of neurotoxin on the physiological processes needed for the generation of an action potential and subsequent muscle contraction would allow better estimates on the physiological toxicity of a nerve agent and its impact on an organism.

The goal of this research was to assist the future development of a unified model and simulation of the chemical kinetics and electrical dynamics occurring in the synaptic cleft during acetylcholinesterase inhibition by neurotoxins. The first objective towards the goal of this research was to develop an accurate and useful model of the kinetics of acetylcholinesterase inhibition that can be simulated and coupled to the voltage and current signals generated by a neuron. A one dimensional diffusion model was used which took advantage of geometric symmetry to focus on the dominant transport effects.

It will be shown that the simulation herein can reproduce the work of earlier research in depicting the time and spatial course of a normal action potential, and the time and spatial course of action potentials influenced by different degrees of acetylcholinesterase inhibition. This is the first simulation to achieve a model of acetylcholinesterase inhibition during the diffusion of a neuro-toxic inhibitor into the neuromuscular junction, and show the altered subsequent action potentials. Also illustrated will be how this simulation could detect the time and space dynamics of moving concentration gradients in the neuromuscular junction under suitable conditions. In addition, an in vivo simulation of inhibited acetylcholinesterase being returned to the active state through the kinetics of pralidoxime therapy will be shown. The mathematical method used in these simulations easily generalizes to a complete three dimensional transport model of the diffusion-reaction processes occurring in the neuromuscular junction.

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