NEUROMUSCULAR TRANSMISSION PROPERTIES OF OCULAR MUSCLE

眼肌的神经肌肉传输特性

• 批准号: 6225380
• 负责人: HENRY J KAMINSKI
• 金额: $ 19.13万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6225380
• 关键词: action potentials; binding sites; cholinergic receptors; electron microscopy; electrophysiology; extraocular muscle; eye movements; fluorescence microscopy; genetically modified animals; laboratory mouse; light microscopy; membrane channels; microelectrodes; neuromuscular disorder; neuromuscular junction; neuromuscular transmission; receptor expression; sodium channel; synaptic vesicles

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.

眼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，眼外神经肌肉接头受到高刺激率，这将导致其他骨骼肌接头的传递失败。 我们假设眼外肌突触的结构特点和离子通道的特点，使他们适应高频率的刺激。 尽管眼外肌能够维持可靠的神经肌肉传递，但其易患神经肌肉传递疾病。 这类疾病的特点是在传播的安全系数上妥协。第一个具体目标是表征眼外肌终板的超微结构特征，已知这些特征有助于其他骨骼肌的安全系数。 第二个目标定义乙酰胆碱受体和钠通道的密度，这是终板电位的主要决定因素。 具体目标三利用直接电生理记录来定义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-功能相关性，以了解允许这些连接保持高放电频率的机制。 允许眼外肌连接处承受极快的放电频率的特性可能使它们在连接处发生疾病时容易受到损害。 最后一个目标是通过形态学、离子通道和功能分析来评价神经肌肉传递障碍转基因小鼠模型的病理学。 通过了解增强眼外肌接头处神经肌肉传递的机制，有可能开发出改善受神经肌肉传递障碍影响的其他接头处传递的方法。 此外，在眼肌连接处的错乱传输的破坏性视觉后果可以逆转。