Preservation of timing in plastic auditory pathways

握持的神经末梢的大花瓣是计算声源的电路中的关键元件 哺乳动物听觉脑干的定位。从这个突触输出动作电位的精确时间 被认为是这项任务的核心。然而，调节和保存动作电位的机制 高频发射过程中的时间安排还不是很清楚。第一个要检验的假设是 神经递质(谷氨酸)的释放效率在发育过程中因释放的变化而变化 概率，由突触前动作电位波形和钙缓冲控制。我们有 研究发现，动作电位波形在动作电位的成熟过程中变得更快、持续时间更短。 霍尔德的花萼。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 沟通随着年龄的增长而变化。我们还将测试假设，可随时释放的池的大小 在突触成熟期间，突触小泡增加，以补偿伴随而来的突触小泡的减少 释放概率。第二个假设是扩散在谷氨酸快速清除中起主要作用。 而代谢性谷氨酸受体(MGluRs)在 未成熟的突触充当自身受体，限制谷氨酸的释放。谷氨酸摄入过多 对大脑是有毒的，它还可能通过使离子受体脱敏来扰乱突触传递， 因此，我们认为mGluRs在发育早期可能起到神经保护作用，限制谷氨酸 在神经胶质细胞还未成熟的时候释放。第三种假说认为，Na/K ATPase在 在高频下保持动作电位的能力中的作用。我们将确定 不同亚型Na/K-ATPase的定位及其功能如何影响突触前和突触 突触后生理学。听觉系统消耗的葡萄糖是人脑中最高的。 大脑中的大部分能量被Na/K-ATPase消耗，因为它恢复和维持离子 Na和K离子在质膜上的梯度。据推测，这是因为它异常高的 听觉脑干和大脑皮层消耗大量的三磷酸腺苷，主要通过 Na/K-ATPase的操作。然而，由于突触前Na/K*-ATPase的性质尚不清楚 到大多数CMS神经末梢的小尺寸。关于它的位置、亚型和功能也知之甚少 听觉通路中Na/K-ATPase的特性通过特异性阻断Na*/K-ATPase 当神经元饥饿时，我们将模拟缺血和中风的影响的药物 氧气和葡萄糖。因此，这项研究提案将产生关于 大脑能量消耗的关键组成部分。

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.