Developmental profile of glutamate receptors in nucleus laminaris

描述（由申请人提供）：理解听觉发展需要了解影响神经结构和功能个体发生的事件。本研究将探讨谷氨酸及其受体在双耳听觉回路中的发育作用。层状核（NL）是鸟类的三级听觉结构，为解决这一问题提供了一个理想的模型系统。NL接收来自大细胞核的兴奋性信息，这些谷氨酸输入在功能上为声音定位提供了初始线索。目前尚不清楚嗜离子性谷氨酸受体（iGluRs）在NL中的发育方式，更重要的是，它们在突触发生、突触完善和树突树突形成中发挥的功能作用。本研究将描述AMPA-和nmda -型谷氨酸受体（AMPA- r和NMDA-R）的发育特征，并确定其生物物理反应特性的发育变化如何影响NL神经元的结构和功能。我提出的研究将涉及突触发育的一般问题。NL突触谷氨酸传递和受体功能的特性和发育意义是什么？我的假设是：(1)NL中的兴奋性突触后电流（EPSCs）由AMPA-和NMDA-Rs介导；(2)AMPA-和NMDA-Rs的生物物理特性在发育和拓扑上受到调节；(3)NMDA-Rs介导的活性对NL的结构和功能至关重要。验证这些假设的具体目的是：(1)表征NL中突触iGluR的发育和拓扑功能；(2)阻断NMDA-R活性，表征NL的结构和功能变化。我将使用的测试这些目标的一般方法是急性脑干切片的全细胞电压钳记录，iGluRs的药理学操作以及培养脑干切片的NMDA-R失活。Lay description：本研究旨在研究发育过程中的兴奋性事件如何在负责双耳听力的听觉神经元之间建立联系。了解这些事件如何影响听觉特性的发展，可能有助于改善在生命早期被剥夺听觉信息的个体的适当治疗。

DESCRIPTION (provided by applicant): Understanding auditory development requires knowledge of events that influences the ontogeny of neural structure and function. This research will examine the developmental role of glutamate and its receptors in a circuit used for binaural hearing. Nucleus laminaris (NL), a third-order auditory structure in birds, provides an ideal model system to address this issue. NL receives excitatory information from nucleus magnocellularis and functionally, these glutamatergic inputs provide initial cues for sound localization. It is unclear how ionotropic glutamate receptors (iGluRs) develop in NL and more importantly, the functional role they play in synaptogenesis, synaptic refinement, and dendritic arborization. This research will characterize the developmental profile of the AMPA- and NMDA-type glutamate receptors (AMPA-R and NMDA-R, respectively) and determine how developmental changes in their biophysical response properties influence the structure and function of NL neurons. My proposed research will address a general question of synaptic development. What are the properties and developmental significances of glutamate transmission and receptor function at NL synapses? My hypotheses are: (1) excitatory postsynaptic currents (EPSCs) in NL are mediated by both AMPA- and NMDA-Rs, (2) biophysical properties of AMPA- and NMDA-Rs are regulated developmentally and tonotopically and (3) activity mediated by NMDA-Rs is essential for NL structure and function. The specific aims to test these hypotheses are: (1) characterize synaptic iGluR function developmentally and tonotopically in NL and (2) block NMDA-R activity and characterize structural and functional changes in NL. The general methods I will use to test these aims are whole-cell voltage clamp recordings from acute brainstem slices, pharmacological manipulations of iGluRs, and NMDA-R inactivation from culture brainstem slices. Lay description: The proposed research studies how excitatory events during development establish connections between auditory neurons responsible for binaural hearing. Understanding how these events influence the development of auditory properties may contribute to the improvement of appropriate therapies for individuals deprived of auditory information early in life.