Mechanisms Regulating Synaptic Function in the Developing Auditory System

发育中听觉系统突触功能的调节机制

• 批准号: 9096738
• 负责人: Jason Tait Sanchez
• 金额: $ 15.45万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096738
• 关键词: Acoustic Nerve; Action Potentials; Address; Auditory; Auditory Perceptual Disorders; Auditory system; Biochemical; Biological; Biological Assay; Biological Models; Birds; Brain; Brain Stem; Brain region; Cell Nucleus; Chickens; Child; Cochlear nucleus; Code; Communication; Comprehension; Cues; Development; Disease; Education; Electrophysiology (science); Embryo; Excitatory Postsynaptic Potentials; Functional disorder; Gene Expression; Genetic; Glutamate Receptor; Glutamates; Goals; Health; Hearing; Language; Learning Disabilities; Light; Mediating; Methods; Molecular; Molecular Target; N-Methylaspartate; Neurons; Neurotransmitters; Noise; Noise-Induced Hearing Loss; Outcome; Pathology; Pharmaceutical Preparations; Plasmids; Play; Presbycusis; Prevalence; Process; Property; Regulation; Research; Role; School-Age Population; Sound Localization; Speech; Speed; Synapses; Synaptic Transmission; System; Testing; Time; Tinnitus; Tissues; Training; Vertebrates; base; biophysical properties; design; genetic manipulation; hatching; improved; in vitro Assay; innovation; knock-down; patch clamp; postsynaptic; protein expression; receptor; relating to nervous system; research study; response; sound; synaptic function; synaptogenesis; vector; voltage clamp

 DESCRIPTION (provided by applicant): The goal of this research is to identify mechanisms that give rise to fast neural encoding of sound critical for normal auditory function. However, developmental mechanisms are poorly understood in the brainstem, where deficits in fast neural encoding underlie aspects of auditory temporal processing disorders. At mature auditory synapses, fast neural encoding is mediated by AMPA-type glutamate receptors (AMPA-Rs) due largely in part to their subunit arrangement, which is distinct from other brain regions. Their unique subunit arrangement raises important biological questions: are the mechanisms that regulate the development of specialized AMPA- R properties in the auditory system similar to mechanisms that regulate AMPA-Rs elsewhere in the brain? If so, what mechanisms govern this different arrangement of AMPA-R subunits? If not, are alternative mechanisms regulating AMPA-Rs exclusive to the auditory system? This study will address these questions by investigating the regulation of synaptic AMPA-Rs properties in the avian auditory brainstem. Elsewhere in the developing brain, NMDA-Rs assist in regulating normal AMPA-R properties and during specific diseased states; NMDA-Rs are implicated as a molecular target in controlling synaptic AMPA-R dysfunction. NMDA-Rs also play a negative role in diseases of the auditory system, including tinnitus, noise- induced hearing loss and neural presbycusis. However, the causal role NMDA-Rs plays in regulating synaptic AMPA-Rs and the extent to which they contribute to fast neural encoding of sound in the developing auditory brainstem are not known. This study will test the hypothesis that the establishment of fast neural encoding requires NMDA-R dependent regulation of synaptic AMPA-R properties in the developing brainstem, critical for precise auditory temporal processing abilities. Investigating the regulator role of NMDA-Rs on AMPA-Rs will be a significant first step in understanding pathologies associated with auditory temporal processing disorders. Using innovative methods, the project aims to determine the extent to which NMDA-Rs (1) regulate the number and subunit composition of synaptic AMPA-R in the developing avian nucleus magnocellularis (NM) and (2) to determine the extent to which temporal speed and precision are mediated by AMPA-Rs at functionally mature NM synapses following genetic manipulation of NMDA-Rs. I will combine in-ovo genetic manipulations, pharmacological/biochemical assays, and in-vitro patch clamp electrophysiology to test the above Aims during developmental time periods corresponding to synapse formation, hearing onset, and functional maturation. Gaining an understanding of NMDA-Rs contribution to synaptic development and refinement should shed light on the role of subunit-specific AMPA-Rs in the auditory system. A better understanding of molecular-level NMDA-R mechanisms may identify pharmacological targets to improve disorders in which synaptic AMPA-R dysfunction has either a direct or causal role in pathologies related to auditory temporal processing.

 描述（由适用提供）：这项研究的目的是确定引起正常听觉功能至关重要的声音的快速神经编码的机制。然而，在脑干中，发育机制的理解很少，在脑干中，在快速的神经编码中定义了听觉临时处理障碍的基础。在成熟的听觉突触中，快速神经编码是由AMPA型谷氨酸接收器（AMPA-RS）介导的，这主要是由于其亚基排列的部分原因，这与其他大脑区域不同。他们独特的亚基安排提出了重要的生物学问题：是否调节在听觉系统中专门的AMPA-R性质开发的机制类似于调节大脑其他地方AMPA-RS的机制？如果是这样，哪些机制控制了AMPA-R亚基的这种不同的安排？如果没有，是否有听觉系统专有地重新计算AMPA-RS的替代机制？这项研究将通过调查鸟类听觉脑干中突触AMPA-RS特性的调节来解决这些问题。在发育中的大脑其他地方，NMDA-RS有助于调节正常AMPA-R特性以及在特定患病状态下； NMDA-RS作为控制突触AMPA-R功能障碍的分子靶标。 NMDA-RS在听觉系统的疾病中也发挥了负面作用，包括耳鸣，噪声引起的听力损失和神经元的长期。然而，因果关系NMDA-RS在调节突触AMPA-RS中发挥作用，以及它们在发育中的听觉脑干中对声音的快速神经元编码的贡献的程度尚不清楚。这项研究将检验以下假设：建立快速神经元编码需要NMDA-R依赖性调节发育中的脑干中突触AMPA-R性质的调节，这对于精确的听觉临时处理能力至关重要。研究NMDA-RS对AMPA-RS的调节剂的作用将是理解与听觉临时处理障碍相关的病理学的重要第一步。该项目使用创新的方法来确定NMDA-RS（1）在发展中的NMDA-RS（1）调节突触AMPA-R的数量和亚基组成中，在发育中的鸟核核细胞核（NM）和（2）中，确定临时速度和精确的程度，以临时NM NM NM nm nm nm Manipucation nm Manipucation nm Manipucation nm Manipucation nm Manipucation nm Manipucation nm Manipucation rampa-rs介导的临时速度和精确介导。我将结合摩擦内的遗传操作，药物/生化测定和体外贴片夹夹电生理学，以在与突触形成，听力发作和功能成熟相对应的发育时期内测试上述目标。了解NMDA-RS对突触开发和改进的贡献，应阐明亚基特异性AMPA-RS在听觉系统中的作用。更好地了解分子级NMDA-R机制可以鉴定出药物靶标，以改善合成AMPA-R功能障碍在与听觉临时处理相关的病理学中具有直接或因果作用的疾病。