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Modulation of Exocytosis and Excitability in Mature Auditory Brainstem Neurons

成熟听觉脑干神经元胞吐作用和兴奋性的调节

基本信息

批准号：
8432349
负责人：
HENRIQUE Prado VON GERSDORFF
金额：
$ 34.77万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432349
关键词：
AMPA Receptors Action Potentials Adult Affect Age Animals Auditory Brain Brain Stem Buffers Cell Nucleus Cells Computer Simulation Coupling Data Dendrites Docking Egtazic Acid Event Excitatory Postsynaptic Potentials Exhibits Exocytosis Fiber Fire - disasters Frequencies Future Glutamates Hearing Hearing problem Imagery Imaging Techniques Indium Lead Length Measures Medial Membrane Mus Nerve Neurons Output Phosphorus 32 Physiological Play Procedures Property Research Resolution Rodent Role Ryanodine Signal Transduction Slice Sound Localization Source Speed Staging Stimulus Structure-Activity Relationship Synapses Techniques Temperature Testing Time Training Vesicle Weaning Work aging population auditory pathway channel blockers hearing impairment improved insight juvenile animal mature animal mouse development myelination neuronal cell body neurotransmitter release novel patch clamp postnatal postsynaptic presynaptic prevent public health relevance ranpirnase sound synaptic depression transmission process trapezoid body treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The large calyx of Held nerve terminal is a pivotal element in the circuitry that computes sound source localization in the mammalian auditory brainstem. Precise timing of action potential output from this synapse is thought to be central for this task. However, the synaptic mechanisms that modulate and preserve action potential timing during high frequency firing are not well understood in mature animals because of the difficultly of recording and visualizing neurons in the heavily myelinated adult brainstem. Our lab has pioneered patch clamp recordings in brainstem slices from more mature and adult-like stages of mouse development, when they fully acquire their fine-tuned ability to hear and localize sound. The first hypothesis to be tested is that the large amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) observed in mature calyx of Held synapses is due to a highly synchronous form of multiquantal release. We suggest that these large and multiquantal mEPSCs are a natural consequence of the progressively tighter coupling of Ca2+ channels to docked vesicles as the synapse matures. We will reconstruct the active zones of mature calyces at a resolution of 3-5 nm and correlate this information with our quantal analysis at the single vesicle exocytosis level. Novel insights into the structure and function relationship of auditory synapses will thus be revealed. The second hypothesis to be tested is that a fast Ca2+-dependent recruitment of vesicles from a reserve pool, triggered by the opening of presynaptic Ca2+ stores, produces a transient EPSC enhancement, or a late-tetanic rebound, during a stimulus train in more mature synapses. We will test this hypothesis by using pharmacological approaches that either block increases in Ca2+ concentration or block the Ca2+ stores from releasing Ca2+. The third hypothesis to be tested is that postsynaptic MNTB principal cell dendrites play a major role in shortening the excitatory postsynaptic potential (EPSP) decay. We hypothesize that this "dendritic speeding" of the evoked EPSP enhances the precision of postsynaptic spikes triggered by afferent fiber stimulation at high frequencies. Finally, to study the passive and active properties of the adult-like MNTB principal cells and their dendrites we will use patch-clamp and Ca2+ imaging techniques. This will allow us to build realistic computer models of how the MNTB cell integrates synaptic inputs and fires action potentials to preserve the timing of incoming sound signals.

描述（由申请人提供）：hold神经末梢的大花萼是哺乳动物听觉脑干中计算声源定位的电路中的关键元件。从这个突触输出动作电位的精确时间被认为是中枢