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，某些类别的这些受体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，这些受体的功能还不清楚。我们建议利用一个可访问的和良好的研究听觉突触，萼举行，探索的行动机制，调制，和几个新的突触前受体的生理功能。大多数注意力将给予突触前甘氨酸受体（GlyR），它介导的兴奋性递质谷氨酸的释放增加，通过去极化的盏神经末梢。在使用膜片钳技术的实验中，我们将对比这些受体在肾盏和突触后细胞中的生物物理特性，以获得亚基组成的证据。此外，我们将确定这些受体在小鼠突变体中的特性，这些突变体在受体的特定亚基中具有缺陷。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它们更好地了解的突触后对应物一起发挥作用。先前的数据表明，GABAA受体在GlyR表达后下调，表明其表达或靶向机制中的偶联。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功能的丧失是否对GABA能传递产生影响。最后，我们将探讨在萼末端，这似乎有不同于传统的突触后NMDA受体的属性的NMDA响应的属性。总之，这些研究应该显着扩大了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靶点，用于选择性控制听觉信号的处理。

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.