CELL INTERACTIONS IN THE DEVELOPING AUDITORY SYSTEM

发育中的听觉系统中的细胞相互作用

• 批准号: 6193622
• 负责人: THOMAS N PARKS
• 金额: $ 35.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-03-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193622
• 关键词: AMPA receptors; auditory nuclei; auditory pathways; calretinin; cell cell interaction; chick embryo; chickens; cochlear nerve; developmental neurobiology; electrophysiology; glutamate receptor; immunofluorescence technique; neural information processing; neurogenesis; otocyst /otolith; protein structure function; tissue /cell culture; western blottings

The encoding of the temporal structure of sounds created in the brainstem auditory system is thought to underlie the representations of the units of speech and the locations of sound sources in the auditory cortex. Brainstem auditory neurons show several specializations that allow them to maintain and transmit precisely the timing information contained in sounds. One of the most important of these adaptations is synaptic glutamate receptors of the AMPA subtype with very rapid desensitization kinetics. The AMPA receptor structure that allows very rapid kinetics also allows high permeability of the receptor-gated ion channel to calcium. To regulate their intracellular calcium concentration within the narrow limits consistent with normal cellular function, auditory neurons employ several calcium- regulating mechanisms, including high levels of the calcium- binding protein calretinin. The characteristic features of AMPA receptors in auditory neurons develop after the onset of spontaneous electrical activity and synaptic function in the auditory pathway. During the same period in development, calretinin becomes localized beneath the cell membrane of auditory neurons, greatly enhancing this molecule's calcium- buffering capacity. The proposed experiments, grouped into two specific aims, will make manipulations of synaptic input to developing auditory neurons 1) in vivo by early deafening or pharmacologic blockade of activity, and 2) in vitro by synaptic pairing of auditory neurons with either auditory or non-auditory partners under different levels of spontaneous activity. The effects of these different developmental environments on AMPA receptor structure and function will be assessed by mRNA analysis, immunology, and electrophysiology. The effects on localization of calretinin will be assessed by quantitative immunohistofluorescence. These experiments will characterize the interacting developmental programs of AMPA receptors and calretinin and assess the influence of afferent synaptic connections and activity on the development of the specialized information-processing and calcium-regulating capacities of brainstem auditory neurons.

脑干听觉系统中产生的声音的时间结构的编码被认为是听觉皮层中语音单位和声源位置表示的基础。 脑干听觉神经元表现出多种特化，使它们能够精确地维持和传输声音中包含的计时信息。 这些适应中最重要的一种是具有非常快的脱敏动力学的 AMPA 亚型突触谷氨酸受体。 AMPA 受体结构允许非常快速的动力学，也允许受体门控离子通道对钙的高渗透性。 为了将细胞内钙浓度调节在与正常细胞功能一致的狭窄范围内，听觉神经元采用多种钙调节机制，包括高水平的钙结合蛋白钙结合蛋白。 听觉神经元中 AMPA 受体的特征是在听觉通路中自发电活动和突触功能开始后形成的。 在发育的同一时期，钙视网膜蛋白定位于听觉神经元的细胞膜下方，大大增强了该分子的钙缓冲能力。 拟议的实验分为两个具体目标，将操纵发育中听觉神经元的突触输入：1）在体内通过早期震耳欲聋或药物阻断活性，2）在体外通过听觉神经元与听觉或非听觉神经元的突触配对。不同水平的自发活动下的听觉伙伴。 这些不同发育环境对 AMPA 受体结构和功能的影响将通过 mRNA 分析、免疫学和电生理学进行评估。 将通过定量免疫组织荧光评估对钙视网膜蛋白定位的影响。 这些实验将表征 AMPA 受体和钙结合蛋白的相互作用发育程序，并评估传入突触连接和活动对脑干听觉神经元专门信息处理和钙调节能力发育的影响。