This application calls for the continued study of excitability and synaptic function in mechanosensory hair cells of the chicken inner ear, especially concerning the role of voltage-gated ion channels. A new venture will involve extending these efforts to hair cells of the mouse cochlea. The regulated expression of voltage-gated calcium channels supports transmitter release, while associated calcium-activated (BK) potassium channels help to shape the receptor potential arising during transduction. The proposal seeks to understand the mechanisms that contribute to ion channel function and their role in synaptic transmission by the hair cell. The investigators will continue to probe the molecular composition of BK potassium channels in chick hair cells. They suggest that both alternative splicing of the alpha subunit, and modulation by accessory beta subunits contribute to the cell-specific kinetics of these channels. Thus, the investigators will seek further evidence for the differential distribution of beta subunits and of alpha subunits splice unit variants in the mature and developing cochlea of the chick. Single channel recording will be used to determine if the gating of native BK channels is consistent with the known influence of the beta subunit. Histological techniques and quantitative RT-PCR will be used to chart the distribution and development of specific alpha and beta channel subunits. This application also proposes extend the studies to mammalian hair cells by making voltage clamp recordings in an excised preparation of the mouse cochlea. The investigators will examine the genesis of spontaneous activity in neonatal spiral ganglion neurons, characterize the biophysics and pharmacology of synaptic currents in afferent neurites at the bases of inner hair cells, quantify the relationship between hair cell calcium current and transmitter release, and determine how that varies with cochlear position and developmental age. These studies promise to further our understanding of the molecular physiology of cochlear hair cells. Further, the regulated expression of ion channels provides a window into the mechanisms that determine hair cell differentiation. The inclusion of the mouse model in this work tests the generality of these mechanisms among vertebrates, and provides an essential basis for the implementation of such studies in transgenic animals.
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