(provide by applicant) Auditory nerves may fire at high frequency for a long time upon sound stimulation. This high frequency firing is relayed with precise timing via synapses up to the auditory brainstem nuclei for sound information processing. To achieve this task, synapses must maintain transmitter release throughout the train of firing. The mechanism underlying sustained transmitter release during repetitive stimulation is not well understood at auditory synapses. I propose a new model to account for sustained transmitter release at auditory synapses. This model is composed of three hypotheses. First, sustained release during repetitive stimulation is due to both a rapid replenishment of a pool of vesicles immediately available for release (releasable pool) and a decrease in the fraction (F) of this pool being released by each impulse. The decrease in F may allow the synapse to sustain transmitter release for a longer time because it slows the rate of depletion of the releasable pool during repetitive stimulation. Secondly, the decrease in F is caused by a decrease in the affinity of the release machinery to Ca2+ Thirdly, replenishment is rapid, but independent of the stimulus intensity and Ca2+ We will test these three hypotheses with three aims, respectively, at a calyx-type synapse in the medial nucleus of the trapezoid body in the rat auditory brainstem. We will monitor membrane capacitance at the nerve terminal, which allows for more direct measurements of the releasable pool size and F. We will determine whether sustained release and relay of action potentials during high frequency firing rely on both a decrease in F and rapid replenishment of the releasable pool (Aim 1). We will increase the Ca2+ concentration by photolysis of the caged Ca2+ compound and determine whether the affinity of the release machinery to Ca2+ is decreased during repetitive stimulation (Aim 2). Finally, we will determine whether the rate of replenishment is regulated by the frequency and duration of stimulation, by the Ca2+ buffer EGTA, or by an increase in the basal Ca2+ concentration induced by photolysis of the caged Ca2+ compound (Aim 3). These studies will improve our understanding of hearing mechanisms by revealing mechanisms underlying sustained transmitter release durng repetitive firing, which is critical for conveying sound information
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