Pharmacology of Neurotransmitters in Hair Cell Organs

描述(申请人提供)：我们的长期目标集中在了解突触传递和耳蜗神经递质。在本项目期间，我们将重点研究传入信息传递的动态调节及其在实现听觉刺激编码的一些显著特征中所起的作用。当人们认为这一过程是由毛细胞释放神经递质包介导的，并且听神经纤维的整个输入都在单个突触中编码时，听觉神经元中编码的时间精度和动态范围是令人惊讶的。在单个突触中实现这些刺激编码能力需要许多特化，其中至少必须有一些强大的机制来随着时间的推移调节突触的强度。我们将应用理解CMS中谷氨酸能突触的最新进展来研究听觉传递的动态调节。首先(目标1)，我们将探讨听觉神经元突触膜上谷氨酸(AMPA)受体的存在是动态调节的假设，并将重点放在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，听觉神经元中AMPA受体的调节很强。其次(目标2)，我们将检验一种假设，即递质释放可能通过激活与钙诱导的钙释放相耦合的代谢性谷氨酸受体来调节。最后(目标3)，我们将探索听觉传递的生化意义，这一令人惊讶的最近发现，突触带中的主要蛋白质是一种功能酶，一种依赖NAD的D异构体特异性2-羟基酸脱氢酶。突触带是一种与毛细胞上的传入突触相关的不寻常结构。了解突触强度是如何调节的，可能有助于开发这些调节机制可能被激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改进针对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一点是，由于对听觉编码的突触传输的需求远远超过任何其他突触，因此，耳蜗神经传输的几个有趣方面高度发达也就不足为奇了。例如，AMPA受体在时间上的精确度和递质释放机制的适应用于精细控制分级释放。动态和精确调节突触强度的机制可能是基本生物机械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可能导致对理解中枢神经系统传递有用的洞察。

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.