# Modulation of Exocytosis and Excitability in Mature Auditory Brainstem Neurons

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $598,995

## Abstract

PROJECT SUMMARY
The mammalian auditory brainstem contains specialized synapses that preserve the precise timing of action
potential spikes. We propose to study two of these specialized synapses: the large calyx of Held synapse in
the medial nucleus of the trapezoid body (MNTB) and the small bouton-type glycinergic synapses of the lateral
superior olive (LSO), that are linked through the MNTB principal neuron. The long-term goal is to determine the
biophysical properties and structure/function of these two pivotal synapses in the circuitry that computes the
locus of high frequency sounds. We will perform patch clamp recordings in mouse brainstem slices from more
adult-like stages of development, when mice fully acquire their fine-tuned ability to hear and localize sound.
Our preliminary data show that several fundamental aspects of brainstem synapses mature only at postnatal
day 30. We thus propose to study the synaptic delays, synaptic strength and short-term plasticity of adult-like
auditory synapses. The first hypothesis is that adult-like calyx-type nerve terminals in the MNTB contain
heterogeneous and crowded active zones (AZs) with multiple docked vesicles that produce ultrashort delays in
vesicle exocytosis. We will perform detailed ultrastructural reconstructions of the AZs using high-resolution
electron tomography (ET). We plan to identify the major factors that promote short exocytosis delays, such as
a large vesicle pool size, crowded AZs with diffusional barriers for Ca2+ ions and tight vesicle-to-Ca2+-channel
coupling. The second hypothesis is that the timing and strength of glycine release in the LSO change during
postnatal development due to shifts in release probability and the size of the readily releasable pool of
vesicles. We report for the first time that inhibitory postsynaptic currents from LSO neurons are preceded by a
prespike waveform that reflects the synchronous arrival of the presynaptic action potentials at multiple synaptic
boutons. This allowed us to quantify for the first time the synaptic delay of a glycinergic auditory synapse. We
will also test the hypothesis that the temporal precision of spike-evoked glycine release relies on large
multiquantal exocytosis. The third hypothesis to be tested is that during postnatal development the LSO
glycinergic synapse acquires a robust Ca2+-dependent vesicle recruitment mechanism. A sustained steady-
state release of glycine onto the LSO neurons thus effectively blocks their ability to fire spikes in response of
excitatory inputs. Our preliminary LSO data show, surprisingly in contrast to the calyx of Held, that maturing
glycinergic LSO synapses decrease their vesicle pool size and increase release probability. Using confocal
microscopy and genetically encoded Ca2+ indicators, we will image Ca2+ influx at glycinergic boutons, and for
the first time describe, using ET, their 3D ultrastructure at high resolution. Together with our collaborators we
will further validate and stud...

## Key facts

- **NIH application ID:** 10109106
- **Project number:** 5R01DC012938-07
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** HENRIQUE Prado VON GERSDORFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $598,995
- **Award type:** 5
- **Project period:** 2012-12-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109106

## Citation

> US National Institutes of Health, RePORTER application 10109106, Modulation of Exocytosis and Excitability in Mature Auditory Brainstem Neurons (5R01DC012938-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10109106. Licensed CC0.

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