Regulation of Synaptic Vesicle Dynamics in the Auditory System

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 DESCRIPTION (provided by applicant): Our long term goal is to understand the mechanisms of synaptic vesicle release and recovery that permit the accurate encoding of sound over wide dynamic ranges over varying times scales. The calyx of Held/MNTB synapse in the auditory brainstem is a key connection in this pathway since it provides precise timing and activates sustained inhibition to key binaural cell groups. Its large size has made it an experimentally accessible entry point into understanding the mechanisms and function of these synaptic connections. The calyx can be driven by sound at high rates, operates in the background of varying spontaneous firing rates, and yet must be relatively immune to acoustically noisy backgrounds. How is this achieved? Since the presynapse has a finite supply of fusion competent synaptic vesicles (SVs), termed the readily releasable pool (RRP), the release and replenishment of the RRP must be balanced to sustain transmission. Priming, the creation of fusion competent SVs at the active zone (AZ) that can be released in response to action potentials (APs), is a key regulatory pathway that regulates the RRP release and replenishment to sustain transmitter release. Ultimately, the molecular mechanisms that regulate priming underlie efficient release and replenishment of SVs underpins sound encoding. Therefore we aim to define the molecular mechanisms that ensure availability of release competent SVs throughout a wide range of AP firing rates to support the early stages of auditory processing. As release and replenishment of the RRP is necessary in all synapses to encode information over varying timescales, our data will have broad relevance to understanding how synaptic communication leads to information transfer in neural networks.