Cochlear Neurotransmitters

几十年来，我们已经知道谷氨酸受体介导内毛细胞及其传入纤维之间的突触传递，但我们对不同类型的谷氨酸受体对刺激编码和听觉病理的贡献知之甚少。所有四种基本类型的谷氨酸受体（AMPA, kainate，代谢和NMDA）都存在于传入末端，但我们真正了解的唯一一种是AMPA受体，它在该突触中介导瞬时传递。了解这些不同类型的谷氨酸受体如何相互作用以编码声音信号将阐明该突触如何实现其非凡的信息传递能力以及其失效模式如何导致兴奋性毒性听力损失。目标1：不同的谷氨酸受体如何在耳蜗中合作产生声诱发反应？目标2。验证在毛细胞突触中运输和调节色素酸受体的假设。目的3：不同的谷氨酸受体如何参与耳蜗的兴奋性毒性？了解这些感受器在耳蜗功能中的作用，也可能导致改善听力的策略。例如，更深入地了解NMDA受体在耳蜗中的作用可能会导致新的耳鸣疗法。了解贩运可能会导致通过增加传入神经元对听觉刺激的敏感性来改善听力的药物。了解不同的神经递质在耳蜗功能中所起的作用，有助于在未来以再生毛细胞为基础的治疗中制定毛细胞神经再生的策略。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难得的机会，这些问题与理解神经系统中突触的功能有关。耳蜗中神经支配模式的简单和极端组织，加上精确传递感觉信号的能力

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.