Regulation of Synaptic Vesicle Dynamics in the Auditory System

听觉系统突触小泡动力学的调节

• 批准号: 10621329
• 负责人: Samuel Matthew Young
• 金额: $ 32.83万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621329
• 关键词: Actins; Action Potentials; Animal Vocalization; Auditory; Auditory Perceptual Disorders; Auditory system; Automobile Driving; Axon; Behavioral; Binaural; Brain; Brain Diseases; Brain Stem; Cell Nucleus; Cells; Central Auditory Processing Disorder; Cochlear nucleus; Communication; Cytoskeleton; Data; Defect; Electron Microscopy; Evoked Potentials; Frequencies; Glutamates; Goals; Hearing; Hearing problem; Human; Intellectual functioning disability; Kinetics; Knock-out; Knockout Mice; Link; Location; Mammals; Medial; Molecular; Mus; Music; Mutation; Nervous System; Neurons; P-Q type voltage-dependent calcium channel; Pathologic; Pathway interactions; Pattern; Physiological; Presynaptic Terminals; Probability; Process; Publishing; Regulation; Research; Role; Signal Transduction; Slice; Sound Localization; Source; Speech; Speech Perception; Speech Sound; Spike Potential; Stimulus; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Techniques; Testing; Viral Vector; Whole-Cell Recordings; aging population; auditory processing; autism spectrum disorder; conditional knockout; gutless adenoviral vector; in vivo; information processing; insight; mouse model; mutant; negative affect; nervous system disorder; neuropsychiatric disorder; neurotransmission; novel; operation; presynaptic; response; sound; synaptic depression; therapy development; transmission process; trapezoid body; vesicular release; voltage

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.

项目总结/文摘

项目成果

Confocal Imaging and 3D Reconstruction to Determine How Genetic Perturbations Impact Presynaptic Morphology at the Mouse Calyx of Held.

• DOI: 10.21769/bioprotoc.4799
• 发表时间: 2023-09-05
• 期刊: Bio-protocol
• 影响因子: 0.8

VikAD, a Vika site-specific recombinase-based system for efficient and scalable helper-dependent adenovirus production.

• DOI: 10.1016/j.omtm.2021.12.001
• 发表时间: 2022-03-10
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Phillips S;Ramos PV;Veeraraghavan P;Young SM Jr
• 通讯作者: Young SM Jr

Orphan receptor GPR158 controls stress-induced depression.

• DOI: 10.7554/elife.33273
• 发表时间: 2018-02-08
• 期刊: eLife
• 影响因子: 7.7
• 作者: Sutton LP;Orlandi C;Song C;Oh WC;Muntean BS;Xie K;Filippini A;Xie X;Satterfield R;Yaeger JDW;Renner KJ;Young SM Jr;Xu B;Kwon H;Martemyanov KA
• 通讯作者: Martemyanov KA

Presynaptic voltage-gated calcium channels in the auditory brainstem.

• DOI: 10.1016/j.mcn.2021.103609
• 发表时间: 2021-04
• 期刊: Molecular and cellular neurosciences
• 作者: Young SM Jr;Veeraraghavan P
• 通讯作者: Veeraraghavan P

Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming.

• DOI: 10.7554/elife.81505
• 发表时间: 2022-10-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Keine C;Al-Yaari M;Radulovic T;Thomas CI;Valino Ramos P;Guerrero-Given D;Ranjan M;Taschenberger H;Kamasawa N;Young SM Jr
• 通讯作者: Young SM Jr