Cellular Mechanisms of the Vestibular System

描述(申请人提供)：这是一项关于前庭器官中突触传递的持续研究，重点是I型毛细胞及其花冠末端，最近的系统发育研究仅在爬行动物、鸟类和哺乳动物中发现。这些结构仅限于爬行动物和鸟类的中央/纹状体区域。它们在哺乳动物中的重要性与日俱增，表明它们分布在所有器官的神经上皮中。此外，虽然I型和II型毛细胞在啮齿类动物的脊骨中出现的数量大致相同，但I型毛细胞在猴子的脊骨中占主导地位，可能在人类的脊骨中也是如此。这些结构的特殊结构和独特的生理学提出了如何完成突触传递的问题。1)I型毛细胞有一种独特的基侧电流，可能会影响突触传递；2)支持细胞不能完成管家功能；3)花萼末端的几何和电生理对突触电流流向棘波编码器提出了不寻常的要求。关于如何解决这些问题，我们只有零星的知识。然而，由于这些结构在哺乳动物(包括人类)中变得越来越重要，这种知识对于我们理解前庭器官如何处理信息至关重要。临床上，I型毛细胞和/或其末端毛细胞对氨基糖苷类耳毒性和年龄相关性退行性变特别敏感。生理学研究将在海龟的后脊进行，并将与将在大鼠和海龟身上进行的形态学研究相结合。有三个具体目标。1)毛细胞：我们将通过从花萼末端进行全细胞记录来表征I型毛细胞的突触传递。假设I型毛发在低频前庭毛细胞中的神经递质释放可能与高频听觉和振动器官不同。2)稳态：转导过程中毛细胞释放K+离子和谷氨酸神经递质。对于II型毛细胞，支持细胞起到清除这些物质的作用。花萼末端的存在使支持细胞不能以同样的方式作用于I型毛细胞。我们假设I型毛细胞和/或其末端包含这些看家功能。3)突触后机制：我们将探索不同的离子通道和神经递质受体如何塑造突触和棘波活动。需要检验的假设是，花萼的分子组织创建了具有不同功能的独立微域：突触传递、棘波启动和放电规则。

DESCRIPTION (provided by applicant): This is a continuing study of synaptic transmission in vestibular organs with emphasis on the type I hair cell and its calyx ending, phylogenetically recent acquisitions only found in reptiles, birds and mammals. These structures are restricted to central/striolar zones in reptiles and birds. Their increasing importance in mammals is suggested by their distribution throughout the neuroepithelium of all organs. In addition, while type I and type II hair cells occur in approximately equal numbers in rodent cristae, type I hair cells predominate in the cristae of monkeys and possibly of humans. The peculiar structure and distinctive physiology of these structures raise problems as to how synaptic transmission is accomplished. 1) Type I hair cells have a distinctive basolateral current that may compromise synaptic transmission; 2) Housekeeping functions cannot be done by supporting cells; and 3) The geometry and electrophysiology of the calyx ending place unusual demands on the flow of synaptic currents to the spike encoder. We have only fragmentary knowledge as to how these problems are solved. Yet, because these structures become of increasing importance in mammals (including humans), such knowledge is crucial to our understanding as to how vestibular organs process information. Of clinical interest, the type I hair cell and/or its calyx ending are especially sensitive to aminoglycoside ototoxicity and age-related degeneration. Physiological studies will be done in the turtle posterior crista and will be integrated with morphological studies to be done in rats and turtles. There are three specific aims. 1) Hair cells: We will characterize synaptic transmission from type I hair cells by making whole- cell recordings from the calyx ending. The hypothesis is that neurotransmitter release from type I hair in low- frequency vestibular hair cells may differ from high-frequency auditory and vibratory organs. 2) Homeostasis: Both K+ ions and glutamate neurotransmitter are released from hair cells during transduction. In the case of type II hair cells, supporting cells serve to clear these substances. The presence of the calyx ending precludes supporting cells from acting in the same way for type I hair cells. We hypothesize that the type I hair cell and/or its ending subsume these housekeeping functions. 3) Postsynaptic mechanisms: We will explore how various ion channels and neurotransmitter receptors shape synaptic and spiking activity. The hypothesis to be tested is that the molecular organization of the calyx creates separate microdomains with discrete functions: synaptic transmission, spike initiation, and discharge regularity.