Function of voltage sensitive K+ channels in mammalian gray matter axons.

哺乳动物灰质轴突中电压敏感 K 通道的功能。

基本信息

批准号：
8730246
负责人：
Morten Raastad
金额：
$ 19.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2015-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Much of the neuronal damage that occurs during seizures, in stroke and traumatic brain injury is due to excessive extracellular levels of glutamate. The release mechanisms for glutamate are located mostly in boutons on very thin, unmyelinated axons. We know that these grey matter axons (GMAs) release glutamate when depolarized, either by action potentials, by pathological increase in extracellular K+, or by energy deficiency as in stroke, but very little is known about the channels involved, and how they control the membrane potential, including the action potential ('spike'). This lack of knowledge about the electrical events that control GMA function prevents development of treatments aimed at controlling excessive glutamate release. Our goal is to identify mechanisms in GMAs that control the repolarization of the spikes, including their after-potentials, and understand how these mechanisms operate in normal and pathological GMA function. To achieve this we will use a set of electrophysiological tools on hippocampal and cerebellar slices. These include single axon and single neuron recording techniques, excitability testing, and a new, modified grease-gap technique that allows recording of the shape of the GMA spike. Using this repertoire of axon-specific techniques we recently showed that the spike in hippocampal Schaffer collaterals and cerebellar parallel fibers has a depolarizing after-potential, which can explain the hyper-excitability and bursting that sometimes follows individual spikes in these thin axons. These experiments will identify mechanisms in GMAs that control the excitability, and particularly the repolarization of the spike, which is tightly linked to the release probability of glutamate. The experiments may also establish GMAs as potential sites for loss of proper excitability control and help target specifically the mechanisms that control spikes and their after-potentials. This would give alternative drug targets for therapies that often fail, for exampe in stroke, and in 30% of all epilepsies.

描述（由申请人提供）：癫痫发作期间发生的许多神经元损伤，中风和脑外伤是由于细胞外谷氨酸水平过多引起的。谷氨酸的释放机制主要位于胸子上，非常薄，无髓的轴突。我们知道，这些灰质轴突（GMAS）在通过动作电位，通过细胞外K+的病理增加或通过卒中的能量缺乏量去极化时释放谷氨酸，但是对所涉及的通道以及它们如何控制膜电位的信息知之甚少，包括动作电位（“ Spike”）。缺乏对控制GMA功能的电气事件的知识，可以阻止旨在控制过度谷氨酸释放的治疗方法的发展。我们的目标是识别GMA中控制峰值（包括其后电位）的机制，并了解这些机制如何在正常和病理GMA功能中运行。为了实现这一目标，我们将在海马和小脑切片上使用一组电生理工具。这些包括单轴突和单个神经元记录技术，兴奋性测试以及一种新的，修改的油脂间隙技术，允许记录GMA Spike的形状。使用这种轴突特异性技术的曲目，我们最近表明，海马Schaffer侧支和小脑平行纤维的峰值具有去极化后电势，这可以解释这些薄轴突中有时遵循单个尖峰的超脱位性和爆发。这些实验将确定GMA中控制兴奋性的机制，尤其是尖峰的重极化，这与释放概率紧密相关谷氨酸。实验还可以建立GMA作为丧失适当兴奋性控制的潜在部位，并有助于针对控制尖峰及其后电位的机制。这将为经常失败的疗法提供替代的药物靶标，并在所有癫痫发作中为30％。