Synaptic mechanisms in the auditory system

描述（由申请人提供）：神经末梢具有丰富的突触前受体，用于各种递质，并且已知这些受体的某些类别的激活可介导各种药物的作用。然而，在中枢听觉系统中，这些受体的功能尚不清楚。我们建议利用一个可接近的和被充分研究的听觉突触，Held的花萼，来探索几种新的突触前受体的作用机制、调节和生理功能。我们将重点关注突触前甘氨酸受体（GlyR），它通过胼胝体神经末梢的去极化介导兴奋性递质谷氨酸释放的增加。在使用膜片钳技术的实验中，我们将对比这些受体在萼和突触后细胞中的生物物理特性，以获得亚单位组成的证据。此外，我们将确定这些受体在具有特定亚基缺陷的小鼠突变体中的特性。其他实验将确定第二信使通路调节这些受体，以及这些受体的激活如何与它们更知名的突触后对应物协同工作。先前的数据表明，GABAA受体在GlyR的表达下下调，这表明它们的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，我们将探索萼端NMDA反应的特性，这似乎与传统的突触后NMDA受体具有不同的特性。总之，这些研究将显著扩展对听觉脑干突触相互作用的理解，并有可能发现选择性控制听觉信号处理的新药物靶点。

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.