Preservation of timing in plastic auditory pathways

Held神经末梢的大萼是计算声源的电路中的关键元件 在哺乳动物听觉脑干中的定位。这个突触动作电位输出的精确时间 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 在高频点火期间的定时还没有被很好地理解。第一个要检验的假设是， 神经递质（谷氨酸）释放的效率在发育过程中由于释放的变化而变化 概率，这是由突触前动作电位波形和钙缓冲控制。我们有 发现动作电位波形在成熟过程中变得更快，持续时间更短。 赫尔德的花萼。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 沟通随年龄而变化。我们还将检验一个假设，即容易释放的 突触囊泡在突触成熟过程中增加，以补偿伴随的 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 从成熟的萼突触的突触间隙，而代谢型谷氨酸受体（mGluRs）， 未成熟的突触充当限制谷氨酸释放量的自身受体。谷氨酸盐太多了 可能对大脑有毒，也可能通过使离子型受体脱敏而破坏突触传递， 因此，我们认为mGluRs可能在发育早期起神经保护作用，限制谷氨酸 在神经胶质还不成熟的时候释放。第三个假说是Na+/K+ ATP酶在细胞内起主要作用。 在Held的花萼以高频率激发动作电位的能力中起作用。康贝特人将以 Na+/K+-ATP酶不同亚型的位置及其功能如何影响突触前和突触后神经元的功能。 突触后生理学听觉系统消耗人类大脑中最高量的葡萄糖。 大脑中的大部分能量被Na+/K+-ATP酶消耗，因为它恢复和维持了离子通道。 Na+和K* 离子穿过质膜的梯度。据推测，由于其异常高的发病率， 在尖峰脉冲时，听觉脑干和皮层消耗大量的ATP，主要是通过 Na+/K+-ATP酶的操作。然而，突触前Na+/K*-ATP酶的性质是未知的， 大多数CMS神经末梢的小尺寸。关于其位置、亚型和功能也知之甚少 Na+/K+-ATP酶在听觉通路中的性质。通过用特异性阻断Na*/K+-ATP酶， 当神经元处于饥饿状态时， 氧气和葡萄糖。因此，这项研究提案将生成有关 是大脑能量消耗的重要组成部分。

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.