Regulation of Synaptic Vesicle Dynamics in the Auditory System

Project Summary/Abstract
The ability to localize sound sources and detect temporal features of sound is fundamental to
hearing. Encoding this information within the first few auditory processing stations requires
reliable and precise synaptic transmission in response to rapid and large fluctuations of upwards
to the kilohertz range in action potential (AP) firing rates. However, the number of synaptic
vesicles (SVs) available for AP-evoked release is limited. Many auditory brainstems synapses
must sustain fast and repetitive SV release to encode sound information. Therefore, sound
encoding places great demands on the temporal dynamics of SV release and replenishment. A
key step regulating AP evoked SV release is priming, the process that creates fusion competent
SVs in close proximity to voltage-gated CaV2 channels (CaV). The rate of priming and SV
replenishment is highly dependent on the magnitude of presynaptic Ca2+ through CaV2 channels.
Human mutations in the molecules regulating priming result in dysregulation of SV release which
is the cause of many auditory and neurological disorders.
In mammals, the pathway between the globular bushy cells (GBCs) and the medial nucleus of
the trapezoid body neurons (MNTB) is critical for encoding sound localization and temporal
features of sound in music and communication found in animal vocalizations to human speech.
The GBC axon forms the calyx of Held, a glutamatergic presynaptic terminal, that is the sole input
that drives AP spiking in the MNTB. The calyx uses fast SV release kinetics to relay the patterns
of afferent AP spikes in the cochlear nucleus to the MNTB. This, in turn, results in rapid and
precise inhibition of key mono- and binaural cell groups. It is emerging that aberrant MNTB
signaling underlies sound localization and speech perception defects in the aging population and
can contribute to central auditory defects found in neurological disorders. Therefore, our goal is
to delineate the molecular mechanisms regulating the temporal dynamics of SV release and
replenishment required for proper auditory information processing. Given the importance of
priming in synaptic transmission, as well as the pathological consequences of aberrant SV
release, our findings will provide fundamental insights into how information is encoded by the
nervous system and are expected to facilitate the development of treatments for a wide range of
neurological and neuropsychiatric disorders.