NEUROMUSCULAR TRANSMISSION PROPERTIES OF OCULAR MUSCLE

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The ocular motor system is preferentially compromised by neuromuscular transmission disorders. In the course of normal eye movement, the extraocular neuromuscular junctions are subject to high stimulation rates that would produce transmission failure of other skeletal muscle junctions. We hypothesize that extraocular muscle synapses have structural features and ion channel characteristics that adapt them to high frequencies of stimulation. Despite their ability to maintain reliable neuromuscular transmission, extraocular muscle is predisposed to diseases of neuromuscular transmission. The hallmark of such diseases is a compromise in the safety factor for transmission. The first specific aim characterizes ultrastructural features of extraocular muscle endplates that are known to contribute to the safety factor of other skeletal muscles. The second aim defines the density of acetylcholine receptors and sodium channels, which are primary determinants of the endplate potential. Specific aim three utilizes direct electrophysiological recording to define the quantal content, endplate sodium currents, and safety factor of singly-innervated extraocular muscle fibers. Fulfillment of these aims provides direct structural-functional correlation to understand the mechanisms that allow these junctions to maintain high firing frequencies. The properties that permit the extraocular muscle junctions to withstand extremely fast firing frequencies likely make them susceptible to compromise when disease at the junction develops. The last objective evaluates this hypothesis in evaluation of the pathology of a transgenic mouse model of a neuromuscular transmission disorder by morphological, ion channel, and functional analyses. Through understanding of mechanisms that enhance neuromuscular transmission at extraocular muscle junctions, the possibility exists that methods may be developed to improve transmission at other junctions compromised by neuromuscular transmission disorders. Further, the devastating visual consequences of deranged transmission at ocular muscle junctions could be reversed.