Developmental profile of glutamate receptors in nucleus laminaris

描述（由申请人提供）：了解听觉发育需要了解影响神经结构和功能个体发育的事件。这项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），在鸟类的三级听觉结构，提供了一个理想的模型系统来解决这个问题。NL接收来自大细胞核的兴奋性信息，功能上，这些兴奋性输入为声音定位提供了初始线索。目前尚不清楚离子型谷氨酸受体（iGluRs）如何在NL中发展，更重要的是，它们在突触发生，突触细化和树突状分支中发挥的功能作用。本研究将表征AMPA和NMDA型谷氨酸受体（AMPA-R和NMDA-R，分别）的发育概况，并确定其生物物理响应特性的发育变化如何影响NL神经元的结构和功能。我提议的研究将解决突触发育的一般问题。NL突触上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的兴奋性突触后电流（EPSC）由AMPA-和NMDA-Rs介导;（2）AMPA-和NMDA-Rs的生物物理特性受发育和张力性调节;（3）NMDA-Rs介导的活性对NL的结构和功能至关重要。检验这些假设的具体目的是：（1）表征NL中发育和张力性的突触iGluR功能，以及（2）阻断NMDA-R活性并表征NL中的结构和功能变化。我将用来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。铺设说明：这项拟议中的研究研究了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早期听觉信息被剥夺的个体的适当治疗。

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.