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理解耳蜗中的突触传递和神经递质。在这个项目期间，我们将集中在传入传递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。听觉神经元编码的时间精度和动态范围是惊人的，如果考虑到这一过程是由毛细胞释放神经递质包介导的，并且听觉神经纤维的整个输入都编码在单个突触中。在单个突触中实现这些刺激编码能力需要许多专门化，其中最重要的是必须有一些强大的机制来随着时间的推移调节突触强度。我们将应用最新的进展，了解在CMS的听觉神经突触检查听觉传递的动态调节。首先（目的1），我们将探讨谷氨酸（AMPA）受体在听觉神经元突触膜上的存在是动态调节的假说，并将重点放在NMDA和代谢型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，听觉神经元中AMPA受体的调节很强。第二（目标2），我们将检查的假设，递质释放可能是通过激活代谢型谷氨酸受体耦合钙诱导的钙释放调节。最后（目标3），我们将探讨听觉传递的生物化学影响的令人惊讶的最近发现，突触带中的主要蛋白质，一个不寻常的结构与毛细胞上的传入突触，是一种功能酶，NAD依赖性，D异构体特异性2羟酸脱氢酶。了解突触强度是如何调节的，可能有助于开发对这些调节机制可能被诱发的疾病的治疗方法，例如对创伤、耳鸣和梅尼埃综合征的兴奋性毒性反应。这项工作可以为评估和修改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需求远远超过其他任何突触，因此耳蜗中神经传递的几个有趣方面高度发达也就不足为奇了。例子包括AMPA受体的时间精度和发射器释放机制的精细控制分级释放的适应。突触强度的动态和精确调节机制可能是基础生物机制高度适应听觉处理的另一个例子。如果是这样的话，那么对听觉神经元中这些现象的分析和理解最终可能会导致对理解CNS传输有用的洞察力。

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.