Cochlear Neurotransmitters

描述(申请人提供)：我们几十年前就知道谷氨酸受体在内毛细胞及其传入纤维之间介导突触传递，但令人惊讶的是，我们对不同类型的谷氨酸受体在刺激编码和听觉病理中的作用知之甚少。所有四种基本类型的谷氨酸受体(AMPA、海人藻酸、代谢性和NMDA)都存在于传入终末，但我们真正了解的唯一一种受体是AMPA受体，它在这个突触中介导每时每刻的传递。了解这些不同类型的谷氨酸受体是如何与声信号相互作用的，将解释这种突触是如何实现其一些非凡的信息传递能力的，以及它的故障模式如何导致兴奋性听力损失。具体目标是：目标1：不同的谷氨酸受体如何在耳蜗声诱发反应中相互协作？目的2.验证海人藻酸受体在毛细胞突触被运输和调节的假说。目的3：不同的谷氨酸受体如何参与耳蜗区的兴奋性毒性？了解这些受体在耳蜗功能中的作用也可能导致改善听力的策略。例如，更好地了解NMDA受体在耳蜗中所起的作用可能会导致新的耳鸣疗法。了解毒品贩运可能会导致药物的出现，通过增加传入神经元对听觉刺激的敏感性来改善听力。了解不同的神经递质在耳蜗功能中扮演的角色，可能有助于在未来基于再生毛细胞的治疗中开发重新支配毛细胞的策略。最后，了解这些不同的谷氨酸受体在毛细胞传入突触中的作用为理解谷氨酸受体编码的基本问题提供了一个非同寻常的机会，这与理解神经系统中的突触功能有关。耳蜗神经支配模式的简单性和极端组织性，加上精确传递感觉信号的能力 在给突触灌输药物的同时监测反应，使我们能够准确地定位这些受体在体内信号处理中的作用。

DESCRIPTION (provided by applicant): We have known for decades that glutamate receptors mediate synaptic transmission between the inner hair cell and its afferent fiber, yet we know astonishingly little about the contributions of the different types of glutamate receptors to stimulus coding and auditory pathology. All 4 basic types of glutamate receptors (AMPA, kainate, metabotropic, and NMDA) are present on afferent terminals but the only one we really understand well is the AMPA receptor, which mediates moment-by-moment transmission at this synapse. Understanding how these different types of glutamate receptors interact to code acoustic signals will illuminate how this synapse achieves some of its extraordinary information transfer capabilities and how its failure modes can lead to excitotoxic hearing loss. The specific aims are: Aim 1: How do different glutamate receptors cooperate to produce sound-evoked responses in the cochlea? Aim 2. Test the hypothesis that kainate receptors are trafficked and regulated at the hair cell synapse. Aim 3: How do different glutamate receptors contribute to excitotoxicity in the cochlea? Understanding the roles of these receptors in cochlear function could also lead to strategies to improve hearing. For example, a greater understanding of the role NMDA receptors play in the cochlea could lead to new tinnitus therapies. Understanding trafficking could lead to drugs that improve hearing by increasing the sensitivity of afferent neurons to auditory stimuli. Knowledge of the roles that the different neurotransmitters play in cochlear function could help in developing strategies for reinnervating hair cells in future therapies based on regenerating hair cells. Finally, understanding the roles of these different glutamate receptors at the hair cell afferent synapse provides an extraordinary opportunity to understand fundamental issues of glutamate receptor coding with relevance to understanding synaptic function in the nervous system in general. The simplicity and extreme organization of the innervation pattern in the cochlea, coupled to the ability to precisely deliver sensory signals and monitor responses while perfusing the synapse with drugs allows us to precisely address the roles of these receptors in signal processing in vivo.