Synaptic mechanisms in the auditory system

描述（由申请人提供）：神经末梢富含多种递质的突触前受体，众所周知，这些受体中某些类别的激活可介导不同类别药物的作用。然而，在中枢听觉系统中，这些受体的功能尚不清楚。我们建议利用可访问且经过充分研究的听觉突触（Held 花萼）来探索几种新型突触前受体的作用机制、调节和生理功能。最受关注的是突触前甘氨酸受体（GlyR），它通过使肾盏神经末梢去极化来介导兴奋性递质谷氨酸的释放增加。在使用膜片钳技术的实验中，我们将对比肾盏和突触后细胞中这些受体的生物物理特性，以获得亚基组成的证据。此外，我们将确定受体特定亚基存在缺陷的小鼠突变体中这些受体的特性。其他实验将确定哪些第二信使途径调节这些受体，以及这些受体的激活如何与其更知名的突触后对应物协同发挥作用。先前的数据表明，GABAA 受体在 GlyR 表达时下调，表明其表达或靶向机制存在耦合。因此，在发育研究中，我们将检查突变小鼠神经末梢中突触前 GABAA 受体和 GlyR 的协调表达，以确定 GlyR 功能的丧失是否会对 GABA 能传递产生影响。最后，我们将探讨花萼末端 NMDA 反应的特性，该反应似乎具有与传统突触后 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，并有可能确定用于选择性控制听觉信号处理的新药物靶标。

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.