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.
Head motions stimulate vestibular sensory cells to make electrical signals that drive stabilizing reflexes. The proposed research will investigate how signals are transmitted across specialized synaptic contacts between the sensory cells and neurons. Damage to the synapses is likely to contribute to the high incidence of dizziness and disorientation requiring clinical attention. Our experiments should provide insight into this vulnerability and help identify pharmaceutical and prosthetic therapies to restore balance and mobility to patients.
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