Nerve Terminal Regulation in the Cerebral Cortex

描述（由申请人提供）：神经末梢的离子通道活性决定突触前动作电位形状和Ca 2+进入，因此在突触传递的调节中起关键作用。这在新皮层的突触前末梢中特别重要，因为该大脑区域在正常条件下和疾病状态期间在介导高级神经功能中的作用。我们最近开发了一种技术，允许电生理记录从单一的，急性隔离大鼠新皮层神经末梢。该实验室的长期目标是通过直接研究新皮层突触前离子通道来回答有关突触传递的生理和病理生理调节的问题。细胞内[Ca 2 +]（[Ca 2 +]i）的增加是突触处的关键信号，在那里它触发胞吐、可塑性和基因表达。关于细胞内Ca 2+变化的下游信号传导比关于细胞外[Ca 2 +]（[Ca 2 +]o）变化的影响知道得多。然而，[Ca 2 +]o可能会因电活动而发生显著变化。该提议的驱动假设是突触间隙[Ca 2 +]的减少是调节突触功效的重要信号。我们最近在新皮层神经末梢中发现了一种新的基于Ca 2+的信号通路，其由电压敏感性非特异性阳离子（NSC）通道组成，该通道通过[Ca 2 +]o的降低而激活。这一有趣的发现提出了一些问题：检测到[Ca 2 +]o的变化并将其转导为膜电导改变的机制是什么？Ca 2+传感器-NSC通道信号通路是否在神经末梢被其他药物调节？Ca 2+传感器-NSC通道信号通路对突触传递的生理影响是什么？为了回答这些问题，我们计划使用电生理学，药理学和免疫化学技术的组合：1。识别Ca 2+传感器-NSC通道信号通路的组成部分。2.确定Ca 2+传感器-NSC通道信号通路的生理调节剂。3.确定Ca 2+传感器-NSC通道信号通路在突触传递中的作用。本提案的目标是了解[Ca 2 +]o调节皮质神经末梢突触中离子通道活性的机制，并确定此Ca 2+传感器-NSC通道信号通路如何影响新皮质中的突触传递。

DESCRIPTION (provided by applicant): Ion channel activity at the nerve terminal determines presynaptic action potential shape and Ca2+ entry and thus plays a pivotal role in the regulation of synaptic transmission. This is particularly important in the presynaptic terminals of the neocortex, due to this brain region's role in mediating higher neurological function under normal conditions and during disease states. We have recently developed a technique that permits electrophysiological recording from single, acutely isolated rat neocortical nerve terminals. The long-term objective of the laboratory is to answer questions about the physiological and pathophysiological regulation of synaptic transmission by directly studying neocortical, presynaptic ion channels with this technique. An increase in intracellular [Ca2+] ([Ca2+]i) is a critical signal at the synapse where it triggers exocytosis, plasticity and gene expression. Much more is known about signaling downstream of changes in intracellular Ca2+ than about the impact of changes in extracellular [Ca2+] ([Ca2+]o). Yet [Ca2+]o is likely to undergo significant changes as a result of electrical activity. The driving hypothesis for this proposal is that a decrease in synaptic cleft [Ca2+] is an important signal which regulates synaptic efficacy. We have recently discovered a novel, Ca2+-based signaling pathway in neocortical nerve terminals, comprised of a voltage sensitive non-specific cation (NSC) channel activated by decreases in [Ca2+]o. This interesting finding poses a number of questions: what is the mechanism by which changes in [Ca2+]o are detected and transduced to alterations in membrane conductance? Is the Ca2+ sensor-NSC channel signaling pathway modulated by other agents at the nerve terminal? What is the physiological impact of Ca2+ sensor-NSC channel signaling pathway on synaptic transmission? To answer these questions we plan to use a combination of electrophysiological, pharmacological and immunochemical techniques to: 1. Identify the constituents of the Ca2+ sensor-NSC channel signaling pathway. 2. Determine physiological modulators of Ca2+ sensor-NSC channel signaling pathway. 3. Determine the role of the Ca2+ sensor-NSC channel signaling pathway in synaptic transmission. The goals of this proposal are to understand the mechanism by which [Ca2+]o modulates ion channel activity in the synapses of the cortical nerve terminals and to determine how this Ca2+ sensor-NSC channel signaling pathway impacts synaptic transmission in the neocortex.