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Modulation of Exocytosis and Excitability in Mature Auditory Brainstem Neurons

成熟听觉脑干神经元胞吐作用和兴奋性的调节

基本信息

批准号：
10672937
负责人：
HENRIQUE Prado VON GERSDORFF
金额：
$ 59.91万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672937
关键词：
3-Dimensional Action Potentials Adult Age Months Auditory Axon Binaural Biophysical Process Brain Stem Buffers Cell Nucleus Cells Cochlear nucleus Computer Models Confocal Microscopy Contralateral Coupled Coupling Crowding Data Development Diffusion Docking Ear Egtazic Acid Electrodes Exhibits Exocytosis Experimental Models Fire - disasters Frequencies Future Glycine Goals Hearing Hearing problem Heterogeneity Image Invaded Ions Ipsilateral Laser Microscopy Light Link Location Measures Medial Modeling Mus Nerve Neurons Output Physiological Potassium Channel Presynaptic Terminals Probability Reporting Research Resolution Slice Sound Localization Spike Potential Structure Synapses Synaptic Membranes Synaptic Transmission Techniques Testing Time Transgenic Mice Vesicle Visualization auditory pathway binaural hearing biophysical analysis biophysical model biophysical properties channel blockers electron tomography experimental study hearing impairment improved in vivo insight lateral superior olive mature animal nano patch clamp pharmacologic postnatal postnatal development postsynaptic preservation presynaptic reconstruction recruit response sound sound frequency synaptic depression trapezoid body treatment strategy

项目摘要

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 study the physiological relevance of our results using in vivo recordings and computer modeling. The proposed experiments will launch new studies on mature LSO synapse structure/function using electron tomography, patch clamp recordings, and direct Ca2+ imaging of LSO bouton-type nerve terminals.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neuroscience: Faster than kiss-and-run.

神经科学：比接吻就跑更快。

DOI：
10.1038/nature12842
发表时间：
2013
期刊：
Nature
影响因子：
64.8
作者：
Cho,Soyoun;vonGersdorff,Henrique
通讯作者：
vonGersdorff,Henrique

Dysmyelination of auditory afferent axons increases the jitter of action potential timing during high-frequency firing.

DOI：
10.1523/jneurosci.3389-12.2013
发表时间：
2013-05-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Kim JH;Renden R;von Gersdorff H
通讯作者：
von Gersdorff H

Resolving presynaptic structure by electron tomography.