Preservation of timing in plastic auditory pathways

保留可塑性听觉通路的时序

• 批准号: 7321095
• 负责人: HENRIQUE Prado VON GERSDORFF
• 金额: $ 31.36万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321095
• 关键词: AMPA Receptors; ATP phosphohydrolase; Action Potentials; Affect; Age; Auditory; Auditory system; Autoreceptors; Axon; Biological Preservation; Brain; Brain Stem; Buffers; Cell membrane; Cells; Chromosome Pairing; Communication; Computer Simulation; Consumption; Coupling; Data; Development; Diffusion; Electric Capacitance; Electrophysiology (science); Excision; Exocytosis; Fire - disasters; Frequencies; Glucose; Glutamate Receptor; Glutamate Transporter; Glutamates; Hearing; Human; Indium; Ions; Ischemia; Life; Location; Measurement; Membrane; Membrane Potentials; Metabotropic Glutamate Receptors; Molecular; Monitor; Mus; Na(+)-K(+)-Exchanging ATPase; Nerve; Neuroglia; Neurons; Neurotransmitters; Operative Surgical Procedures; Output; Oxygen; Physiological; Physiology; Plastics; Play; Probability; Process; Property; Protein Isoforms; Pump; Rate; Rattus; Research; Research Personnel; Research Proposals; Residual state; Resolution; Role; Shapes; Slice; Source; Stimulus; Stroke; Synapses; Synaptic Cleft; Synaptic Receptors; Synaptic Transmission; Synaptic Vesicles; Temperature; Testing; Thinking; Time; Training; Vesicle; Week; Work; auditory pathway; desensitization; experience; insight; juvenile animal; neurotransmitter release; patch clamp; postnatal; postsynaptic; presynaptic; programs; receptor; size; sound; synaptic depression

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 mechanisms that modulate and preserve action potential timing during high frequency firing are not well understood. The first hypothesis to be tested is that the efficiency of neurotransmitter (glutamate) release changes during development due to changes in release probability, which is controlled by the presynaptic action potential waveform and Ca buffering. We have found that action potential waveforms become faster and shorter in duration during the maturation of the calyx of Held. This will have important consequences for synaptic delays and release probability. We will use computer simulations and electrophysiology to determine how synaptic delays and the strength of synaptic communication varies with age. We will also test the hypothesis that the size of the readily releasable pool of synaptic vesicles increases during synapse maturation in order to compensate for a concomitant decrease in release probability. The second hypothesis is that diffusion plays the major role in fast glutamate clearance from the synaptic cleft of mature calyx synapses, whereas metabotropic glutamate receptors (mGluRs) in immature synapses act as autoreceptors that limit the amount of glutamate release. Too much glutamate can be toxic for the brain, and it may also disrupt synaptic transmission by desensitizing ionotropic receptors, so we propose that mGluRs may play a neuroprotective role early during development, limiting glutamate release at a time when glia are still immature. The third hypothesis is that the Na+/K+ ATPase plays a major role in the ability of the calyx of Held to fire action potentials at high frequencies. We will determine the location of different subtypes of the Na+/K+-ATPases and how their function affects presynaptic and postsynaptic physiology. The auditory system consumes the highest amount of glucose in the human brain. Most of that energy in the brain is consumed by the Na+/K+-ATPase as it restores and maintains the ionic gradients of Na+ and K* ions across the plasma membrane. Presumably due to its unusually high rate of spiking, the auditory brainstem and cortex consume remarkably large amounts of ATP, principally via the operation of the Na+/K+-ATPase. However, the properties of presynaptic Na+/K*-ATPases are unknown due to the small size of most CMS nerve terminals. Little is also known about the location, subtype and functional properties of Na+/K+-ATPases in auditory pathways. By blocking Na*/K+-ATPases with specific pharmacological agents we will mimic the effects of ischemia and strokes, when neurons are starved for oxygen and glucose. Thus, this research proposal will generate basic data and insights on a critical component of energy consumption in the brain.

赫尔德神经末梢的大花萼是计算声源的电路中的关键元件 定位于哺乳动物听觉脑干。该突触动作电位输出的精确计时 被认为是这项任务的核心。然而，调节和保持动作电位的机制 高频发射期间的时间尚不清楚。第一个要检验的假设是 由于释放的变化，神经递质（谷氨酸）释放效率在发育过程中发生变化 概率，由突触前动作电位波形和 Ca 缓冲控制。我们有 发现动作电位波形在成熟过程中变得更快且持续时间更短 持有的花萼。这将对突触延迟和释放概率产生重要影响。我们将使用 计算机模拟和电生理学来确定突触延迟和突触强度 沟通随着年龄的变化而变化。我们还将测试以下假设：易于释放的池的大小 突触小泡在突触成熟期间增加，以补偿伴随的突触小泡的减少 释放概率。第二个假设是扩散在快速谷氨酸清除中起主要作用 来自成熟花萼突触的突触间隙，而代谢型谷氨酸受体（mGluR） 未成熟的突触充当自身受体，限制谷氨酸的释放量。谷氨酸过多 对大脑有毒，还可能通过使离子型受体脱敏来破坏突触传递， 因此我们认为 mGluRs 可能在发育早期发挥神经保护作用，限制谷氨酸 在神经胶质细胞尚未成熟时释放。第三个假设是 Na+/K+ ATP 酶起着主要作用。 在 Held 花萼高频激发动作电位的能力中发挥作用。我们将确定 Na+/K+-ATP酶不同亚型的位置以及它们的功能如何影响突触前和 突触后生理学。听觉系统消耗人脑中最多的葡萄糖。 大脑中的大部分能量被 Na+/K+-ATP 酶消耗，因为它恢复并维持离子 Na+ 和 K* 离子穿过质膜的梯度。大概是由于其异常高的比率 尖峰时，听觉脑干和皮层消耗大量 ATP，主要通过 Na+/K+-ATP酶的操作。然而，突触前 Na+/K*-ATP 酶的特性尚不清楚，因为 大多数 CMS 神经末梢的尺寸都很小。关于位置、亚型和功能也知之甚少 Na+/K+-ATP酶在听觉通路中的特性。通过用特定的方法阻断 Na*/K+-ATP 酶 当神经元饥饿时，我们将使用药物模拟缺血和中风的影响 用于氧气和葡萄糖。因此，本研究提案将产生有关以下方面的基本数据和见解： 大脑能量消耗的重要组成部分。