Synaptic Processing in the Vestibular System

描述（由申请人提供）：前庭毛细胞将头部位置和运动转化为电化学信号，这些信号通过突触传递到传入神经纤维。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。前庭内耳功能的丧失可能是许多需要临床关注的头晕和定向障碍病例的原因， 根据内耳前庭和耳蜗部分的工作，毛细胞和传入神经之间的突触可能是最脆弱的部位。因此，突触是临床上重要的课题。此外，由于其引人注目的形态学和分子特征，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，初级传入纤维形成与II型毛细胞中的突触前带相对的小的终末，加上吞噬一个或多个I型毛细胞的大的萼状终末。这些独特的突触后盏可以接受突触囊泡释放的递质，这些突触囊泡排列在数十个突触带周围。最近的工作表明，在中央（纹状）区的上皮细胞的肾盏承担特别密集的浓度的电压门控钠（Na）和钾（K）通道。在扣和杯上皮区的变化很可能有助于自发和诱发放电之间的差异striolar和extrastriolar（外周区）传入人群。我们将研究从毛细胞传入的传递，在切除的，半完整的感觉上皮的啮齿动物耳石器官。在目标1中，我们将记录对发束（单个或整体）偏转的突触前和突触后反应，以表征突触如何影响机械感觉信号的定时、调谐和水平依赖性。初步结果表明，囊泡（量子）的传输有显着的延迟，萼突触可以传输非量子信号，除了量子信号。我们假设，纹状体突触有多种机制，以提高突触的时间性能和额外的纹状体突触整合空间和时间，以提高在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通道在肾盏和终扣的影响。我们假设，未成熟的终端传输由毛细胞电共振和尖峰驱动的爆发性活动， 通过KLV通道从成熟的纹状体突触中分离出来。我们知道，添加KLV通道的纹状体I型毛细胞在分化过程中大大拓宽了带宽，减少了受体电位的相位滞后，并假设添加KLV通道的纹状体终端同样影响突触后电位。我们将测试是否：KLV通道增强非量子信号和NaLV通道增加的兴奋性的纹状小管。这种成熟的变化可能会产生相位超前，抵消反射通路的相位滞后，甚至在20 Hz以上的头部运动，允许前庭反射补偿。

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.