Synaptic Processing in the Vestibular System

描述(申请人提供)：前庭毛细胞将头部位置和运动转化为电化学信号，通过突触传递给传入神经纤维。这些信号驱动控制凝视、姿势和平衡的反射，也有助于感知方向和自我运动。前庭内耳功能丧失可能是许多需要临床注意的头晕和定向障碍的原因，而 根据内耳前庭和耳蜗部的工作，毛细胞和传入细胞之间的突触可能是最脆弱的部位。因此，突触是一个具有重要临床意义的课题。此外，由于它们惊人的形态和分子特征，它们提供了独特的神经生物学机会。在哺乳动物的前庭器官中，初级传入形成与II型毛细胞的突触前带相对的小突触终末，以及吞噬一个或多个I型毛细胞的大的帽状终末。这些独特的突触后肾盏可能接受排列在数十条突触带周围的突触小泡释放的递质。最近的研究表明，上皮中央(纹状体)区的花瓣承载着特别密集的电压门控钠(Na)和钾(K)通道。纹状体与纹状体外(外周区)传入群体的自发放电和诱发放电的差异可能与纹状体和花盏上皮带的差异有关。我们将在啮齿动物耳石器官的切除的、半完整的感觉上皮细胞中研究毛细胞到传入细胞的传递。在目标1中，我们将记录突触前和突触后对毛束偏转(单个或整体)的反应，以表征突触如何影响机械感觉信号的时序、调谐和水平依赖性。初步结果表明，囊泡(量子)传递有明显的延迟，并且除了量子信号外，帽状突触还可以传递非量子信号。我们假设纹状体突触有多种机制来改善突触的时间性能，纹状体外突触在空间和时间上整合以增强对低刺激频率的敏感性。在目标2中，我们将研究低电压激活(LV)的Na和K通道在肾盏和肾小管上的影响。我们假设，未成熟的终末传输由毛细胞电共振和尖峰驱动的突发性活动，而这些都被消除了 从成熟的纹状体突触通过KLV通道。我们知道，在分化过程中向纹状体I型毛细胞添加KLV通道极大地加宽了受体电位的带宽并减少了相位滞后，并假设向纹状体终末添加KLV通道同样会影响突触后电位。我们将测试：KLV通道是否增强非量子信号，NaLV通道是否增强纹状体花瓣的兴奋性。这种成熟的变化可能会产生相位导联，抵消反射路径的相位滞后，允许通过前庭反射对头部运动进行补偿，即使在20赫兹以上。

DESCRIPTION (provided by applicant): Vestibular hair cells transduce head position and motion into electrochemical signals which they transmit across synapses to afferent nerve fibers. The signals drive reflexes that control gaze, posture and balance and also contribute to perception of orientation and self-motion. Loss of function in the vestibular inner ear is likely responsible for many cases of dizziness and disorientation that require clinical attention, and the synapses between hair cells and afferents may be the most vulnerable site, based on work in both vestibular and cochlear parts of the inner ear. Thus, the synapses are a clinically important subject. In addition, they present a unique neurobiological opportunity because of their striking morphological and molecular features. In mammalian vestibular organs, primary afferents form small bouton terminals opposite pre-synaptic ribbons in type II hair cells plus large calyceal terminals that engulf one or more type I hair cells. These uniquely postsynaptic calyces may receive transmitter released from synaptic vesicles arrayed around dozens of synaptic ribbons. Recent work has shown that calyces in the central (striolar) zone of the epithelium bear especially dense concentrations of voltage-gated sodium (Na) and potassium (K) channels. Variations in boutons and calyces with epithelial zone are likely to contribute to spontaneous and evoked firing differences between striolar and extrastriolar (peripheral-zone) afferent populations. We will study transmission from hair cells to afferents in excised, semi-intact sensory epithelia of rodent otolith organs. In Aim 1, we will record pre- and post-synaptic responses to deflection of hair bundles (single or as ensembles) to characterize how the synapse affects timing, tuning and level dependence of the mechanosensory signal. Preliminary results show that vesicular (quantal) transmission has a significant delay and that calyceal synapses can transmit non-quantal signals in addition to quantal signals. We hypothesize that striolar synapses have multiple mechanisms to improve the temporal performance of the synapse and that extrastriolar synapses integrate spatially and temporally to enhance sensitivity at low stimulus frequencies. In Aim 2, we will investigate the impact of low-voltage-activated (LV) Na and K channels in calyces and boutons. We hypothesize that immature terminals transmit bursty activity driven by hair cell electrical resonances and spikes, which are eliminated from maturing striolar synapses by KLV channels. We know that adding KLV channels to striolar type I hair cells during differentiation greatly broadens the bandwidth and reduces phase lag of the receptor potential and hypothesize that adding KLV channels to striolar terminals similarly affects postsynaptic potentials. We will test whether: KLV channels enhance non-quantal signals and NaLV channels increase the excitability of striolar calyces. Such maturational changes may create phase leads that offset the phase lags of the reflex pathway, allowing compensation by vestibular reflexes for head motions even above 20 Hz.