Electrogenic Modulation of Signal Decoding in Presynaptic Terminals

突触前终末是大脑中的基本计算单位，它们的功能障碍与 患有几种神经系统疾病。它们调节传入电信号的传递(动作 电位)转化为化学信号(神经递质释放)，而转换的效率决定了 记忆和行为背后的电路强度。这项建议的最终目标是理解 突触前细胞机制调节动作的电化学转导机制 潜力。众所周知，突触前终末是高度适应性的结构，能够维持 通过截然不同的输入速率、新陈代谢状态和囊泡融合概率进行传播。我们最近 与其他人的共同工作揭示了这样一个事实，即动作电位并不是不变的信号。一 在轴突分枝内存在着临界水平的调节，它积极地调节轴突的传播和 到达每个突触前终端的电信号的形状。我们假设有一秒钟 在突触前终末存在一套补充的、但目前尚未确定的机制，这些机制迅速 感知细胞状态并改变电信号输入的化学转导。因此， 单个突触前终末瞬间调节其膜的产电特性 通过局部离子通道激活途径，动态调节对给定的化学反应 当它到达时，动作潜力。我们建议确定这种“在飞行中”控制系统的分子基础 转导在以下目标：目标1。我们将确定细胞代谢能量状态如何 突触(ATP/ADP比值)通过ATP敏感性钾通道影响动作电位转导。目标 2.我们将确定刺激频率如何改变突触前电压和钙敏感的激活 钾通道对兴奋性和抑制性终末动作电位转导的影响。 目的3.我们将确定如何将钙通道偶联到囊泡融合释放机械控制 钾通道激活。这些目标的结果将提供有关电产生机制的新数据 影响突触前终末的复杂计算，导致对 突触可塑性和神经元加工。

Presynaptic terminals are fundamental computational units in the brain, and their dysfunction is associated with several neurological diseases. They mediate the transduction of incoming electrical signals (action potentials) into chemical signals (neurotransmitter release), and the efficiency of conversion determines the strength of circuits underlying memory and behavior. The ultimate goal of this proposal is to understand the mechanisms by which presynaptic cellular machineries modulate the electro-chemical transduction of action potentials. It is known that presynaptic terminals are highly adaptive structures capable of maintaining transmission across vastly different input rates, metabolic states, and vesicle fusion probabilities. Our recent work in combination with others has exposed the fact that action potentials are not invariant signals. One critical level of regulation exists within the axonal arborization, which actively regulates the propagation and shape of electrical signals arriving at each of its presynaptic terminals. We hypothesize that a second complementary, but currently uncharacterized, set of mechanisms exist at presynaptic terminals that rapidly sense the cellular state and alter the chemical transduction of electrical signal inputs. As a result, the individual presynaptic terminals instantaneously adjust the electrogenic properties of their membranes through local ion channel activation pathways which dynamically regulate the chemical response to a given action potential as it arrives. We propose to identify the molecular basis of this “on the fly” control system of transduction in the following aims: Aim 1. We will determine how the cellular metabolic energy state of the synapse (ATP:ADP ratio) influences action potential transduction via ATP-sensitive potassium channels. Aim 2. We will determine how stimulation frequency alters the activation of presynaptic voltage- and calciumsensitive potassium channels to influence action potential transduction in excitatory and inhibitory terminals. Aim 3. We will determine how coupling calcium channels to vesicle fusion release machinery controls potassium channel activation. Results from these aims will present new data on electrogenic mechanisms influencing complex computations of presynaptic terminals, leading to a more complete understanding of synaptic plasticity and neuronal processing.