Pharmacology of Neurotransmitters in Hair Cell Organs

描述（由申请人提供）：我们的长期目标集中在了解耳蜗中的突触传递和神经递质。在本项目期间，我们将重点研究传入传输的动态调节及其在实现听觉刺激编码的一些显着特征中的作用。当我们考虑到这个过程是由毛细胞释放神经递质包介导的，并且整个输入到听觉神经纤维的信息都被编码在一个单一的突触中时，听觉神经元编码的时间精度和动态范围是惊人的。在单个突触中实现这些刺激编码能力需要许多专业化，其中最重要的是必须有一些强大的机制来调节突触的强度。我们将应用最近的进展，了解谷氨酸突触在CMS检查听觉传递的动态调节。首先（目的1），我们将探讨听觉神经元突触膜中谷氨酸（AMPA）受体的存在受到动态调节的假设，并将重点关注NMDA和代谢性谷氨酸受体的激活在这一现象中的作用。我们实验室的工作表明AMPA受体在听觉神经元中具有强大的调节作用。其次（目的2），我们将检验一种假设，即通过激活代谢性谷氨酸受体与钙诱导的钙释放耦合来调节递质释放。最后（目的3），我们将探讨最近令人惊讶的发现对听觉传递的生化意义，即突触带中的主要蛋白质是一种功能性酶，一种依赖于NAD的D异构体特异性2羟基酸脱氢酶，这是一种与毛细胞上传入突触相关的不寻常结构。了解突触强度是如何被调节的可能有助于开发对这些调节机制可能被唤起的疾病的治疗方法，如创伤、耳鸣和梅尼埃综合征的兴奋毒性反应。本研究可为评价和改进这些问题的药物治疗提供科学依据。最后，但并非最不重要的是，由于听觉编码对突触传递的要求远远超过任何其他突触，因此在耳蜗中高度发展神经传递的几个有趣方面应该不足为奇。例子包括AMPA受体对时间精度的适应和递质释放机制对分级释放的精细控制。突触强度的动态和精确调节机制可能是基本生物机制高度适应听觉处理的另一个例子。如果是这样，那么对听觉神经元中这些现象的分析和理解最终将有助于理解中枢神经系统的传递。

DESCRIPTION (provided by applicant): Our long-term goals are centered on understanding synaptic transmission and neurotransmitters in the cochlea. In this project period, we will focus on dynamic regulation of afferent transmission and its role in achieving some of the remarkable characteristics of auditory stimulus coding. The temporal precision and dynamic range encoded in auditory neurons is astonishing when one considers that this process is mediated by the hair cell releasing packets of neurotransmitter and that the entire input to the auditory nerve fiber is encoded in a single synapse. The achievement of these stimulus coding capabilities in a single synapse requires a number of specializations, not the least of which must be some formidable mechanisms to regulate synaptic strength over time. We will apply recent advances in understanding glutamatergic synapses in the CMS to examine dynamic regulation of auditory transmission. First (aim 1), we will explore the hypothesis that the presence of glutamate (AMPA) receptors in the synaptic membrane of auditory neurons is dynamically regulated, and will focus on the roles of activation of NMDA and metabotropic glutamate receptors in this phenomenon. Work in our laboratory indicates robust regulation of AMPA receptors in auditory neurons. Second (aim 2), we will examine the hypothesis that transmitter release may be regulated through activation of metabotropic glutamate receptors coupled to calcium-induced calcium release. Finally (aim 3), we will explore the biochemical implications for auditory transmission of the surprising recent finding that the major protein in the synaptic ribbon, an unusual structure associated with the afferent synapse on the hair cell, is a functional enzyme, an NAD dependent, D isomer specific 2 hydroxyacid dehydrogenase. Understanding how synaptic strength is regulated may aid in developing treatments for disorders in which these regulatory mechanism may be evoked, such as excitotoxic responses to trauma, tinnitus, and Meniere's syndrome. This work could provide a scientific basis for evaluating and modifying drug treatments for those problems. Last, but not least, because the demands on synaptic transmission for auditory coding far exceed those at any other synapse, it should not be surprising that several interesting facets of neurotransmission are highly developed in the cochlea. Examples include adaptations of the AMPA receptor for temporal precision and of transmitter release mechanisms for fine control of graded release. Mechanisms for dynamic and precise regulation of synaptic strength may be yet another instance in which basic biological machinery is highly adapted for auditory processing. If so, then analysis and understanding of these phenomena in auditory neurons could ultimately lead to insight useful in understanding CNS transmission.