NEUROMUSCULAR TRANSMISSION PROPERTIES OF OCULAR MUSCLE

眼球运动系统优先受到神经肌肉传递障碍的损害。在正常的眼球运动过程中，眼外神经肌肉连接受到高刺激率的影响，这将导致其他骨骼肌连接的传递失败。我们假设眼外肌突触具有结构特征和离子通道特征，使其适应高频刺激。尽管眼外肌能够维持可靠的神经肌肉传递，但眼外肌容易患上神经肌肉传递疾病。这类疾病的特点是在传播安全系数上妥协。第一个特定的目的是表征眼外肌终板的超微结构特征，这些特征已知有助于其他骨骼肌的安全系数。第二个目的是定义乙酰胆碱受体和钠通道的密度，它们是终板电位的主要决定因素。具体目的三利用直接电生理记录来确定单神经支配的眼外肌纤维的量子含量、终板钠电流和安全系数。这些目标的实现提供了直接的结构-功能关联，以了解允许这些连接保持高放电频率的机制。眼外肌交界处能够承受极快的放电频率，这种特性很可能使它们在交界处疾病发展时容易受到损害。最后一个目标是通过形态、离子通道和功能分析来评估这一假说在一种神经肌肉传递障碍转基因小鼠模型中的病理学。通过了解增强眼外肌交界处神经肌肉传递的机制，有可能开发出方法来改善其他因神经肌肉传递障碍而受损的交界处的传递。此外，眼肌交界处错乱传播的破坏性视觉后果可能会被逆转。

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.