Synaptic mechanisms in the auditory system

听觉系统中的突触机制

• 批准号: 6574715
• 负责人: LAURENCE O TRUSSELL
• 金额: $ 33.31万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574715
• 关键词: GABA receptor; acoustic nerve; auditory pathways; biophysics; electrophysiology; genetically modified animals; genotype; glutamate receptor; glycine receptors; laboratory mouse; laboratory rat; neurotransmitter transport; polymerase chain reaction; receptor coupling; receptor expression; second messengers; synapses; voltage /patch clamp

DESCRIPTION (provided by applicant): Nerve terminals are richly endowed with presynaptic receptors for a variety of transmitters, and activation of some classes of these receptors are well-known to mediate the actions of diverse classes of drugs. In the central auditory system, however, the functions of these receptors is not well understood. We propose to take advantage of an accessible and well-studied auditory synapse, the calyx of Held, to explore the mechanisms of action, the modulation, and the physiological functions of several novel presynaptic receptors. Most attention will be given to the presynaptic glycine receptor (GlyR), which mediates an increase in the release of the excitatory transmitter glutamate by depolarizing the calyceal nerve terminal. In experiments using patch clamp techniques we will contrast the biophysical properties of these receptors in calyces and in postsynaptic cells to gain evidence of subunit composition. Additionally, we will determine the properties of these receptors in mouse mutants having defects in specific subunits of the receptor. Other experiments will determine what second messenger pathways modulate these receptors and how activation of these receptors function in concert with their better known postsynaptic counterparts. Previous data indicate that the GABAA receptors are down regulated upon expression of the GlyR, suggesting a coupling in the mechanisms of their expression or targeting. In developmental studies we therefore will examine the coordinate expression of presynaptic GABAA receptors and GlyR in nerve terminals of the mutant mice, to determine if loss of GlyR function has consequences for GABAergic transmission. Finally, we will explore the properties of an NMDA response in the calyx terminal, which appears to have properties distinct from conventional postsynaptic NMDA receptors. Together, these studies should significantly expand out understanding of synaptic interactions in the auditory brainstem and potentially identify new drug targets for selective control of processing of auditory signals.

描述（由申请人提供）：神经终末属于各种发射器的突触前受体，并且某些类别的这些受体的激活是众所周知的，可以介导各种类药物的作用。但是，在中央听觉系统中，这些受体的功能尚不清楚。我们建议利用可访问且研究充分的听觉突触，即持有的花萼，以探索几种新型突触前受体的作用机理，调节和生理功能。大多数关注会引起突触前甘氨酸受体（GLYR），该甘氨酸受体（GLYR）介导兴奋性发射机谷氨酸的释放增加，方法是通过去极化的小钙神经末端来释放。在使用斑块夹技术的实验中，我们将在钙和突触后细胞中这些受体的生物物理特性对比，以获得亚基组成的证据。此外，我们将确定这些受体在受体特定亚基中缺陷的小鼠突变体中的特性。其他实验将确定哪种第二信使途径调节这些受体，以及这些受体的激活如何与较知名的突触后对应物一起起作用。先前的数据表明，GABAA受体在Glyr表达时被调节，这表明其表达或靶向的机理耦合。因此，在发育研究中，我们将检查突变小鼠神经末端突触前GABAA受体和Glyr的坐标表达，以确定Glyr功能的丧失是否对GABAergic传播产生了影响。最后，我们将探讨花萼末端中NMDA响应的性质，该末端似乎具有与常规突触后NMDA受体不同的特性。总之，这些研究应显着扩展对听觉脑干中突触相互作用的理解，并有可能确定新的药物目标，以选择性控制听觉信号的处理。