This is a competing renewal to continue study of the functional development of cochlear hair cells. The long-term goals of this project are to determine the influence of hair cell physiology on cochlear function during development, with particular attention to activity-- dependent processes. Specifically, this work targets the role of intracellular Ca in the developmental regulation of voltage- and ligand-gated ion channels in hair cells. These questions are central to the broader issue of neural development, and the answers obtained in this work also will provide the basis for future study of ontogenetic hearing disorders. Previous work in this laboratory showed that chick cochlear hair cells were electrically excitable and could display the electrical tuning that supports acoustic frequency selectivity in lower vertebrates. This tuning mechanism arises from the interaction of voltage-gated Ca and Ca-- activated K channels in hair cells. The functional importance of this mechanism in chicks was suggested by the observation that the underlying Ca-activated K current was first observed in late embryonic hair cells, at the time that cochlear function begins to mature rapidly. Voltage-clamp recording from single hair cells will be used to study further the developmental acquisition of ion channels. Hair cells will be isolated from the cochleas of embryonic chicks, or from embryonic cochleas that have been maintained in culture. Normal development will be perturbed by procedures that block or enhance influx through voltage-gated Ca channels or that eliminate intracellular Ca stores. The relationship between hair cell Ca current and transmitter release specializations will be studied by voltage clamp and by labelling synaptic vesicles with an activity-dependent fluorescent dye, or by counting release sites with serial electron microscopy of similar cells. The genetic regulation of ion channel expression will be examined by blocking RNA or protein synthesis in the cochlear cultures. This question will be examined much more specifically by initiating efforts to clone and identify cochlear K channel genes. When identified, the developmental regulation of specific K channel mRNAs will be studied.
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