PDF(Pubmed)
Abstract：
Simultaneous changes in ion concentrations, glutamate, and cell volume together with exchange of matter between cell network and vasculature are ubiquitous in numerous brain pathologies. A complete understanding of pathological conditions as well as normal brain function, therefore, hinges on elucidating the molecular and cellular pathways involved in these mostly interdependent variations. In this paper, we develop the first computational framework that combines the Hodgkin-Huxley type spiking dynamics, dynamic ion concentrations and glutamate homeostasis, neuronal and astroglial volume changes, and ion exchange with vasculature into a comprehensive model to elucidate the role of glutamate uptake in the dynamics of spreading depolarization (SD)-the electrophysiological event underlying numerous pathologies including migraine, ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hematoma, and trauma. We are particularly interested in investigating the role of glutamate in the duration and termination of SD caused by K+ perfusion and oxygen-glucose deprivation. Our results demonstrate that glutamate signaling plays a key role in the dynamics of SD, and that impaired glutamate uptake leads to recovery failure of neurons from SD. We confirm predictions from our model experimentally by showing that inhibiting astrocytic glutamate uptake using TFB-TBOA nearly quadruples the duration of SD in layers 2-3 of visual cortical slices from juvenile rats. The model equations are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles or a combination of these principles and known physiological facts. Accordingly, we claim that our approach can be used as a future guide to investigate the role of glutamate, ion concentrations, and dynamics cell volume in other brain pathologies and normal brain function.
摘要：
离子浓度的同时变化，谷氨酸,和细胞体积以及细胞网络和脉管系统之间的物质交换在许多脑部病理中普遍存在。全面了解病理状况以及正常的大脑功能，因此,取决于阐明这些主要相互依赖的变化所涉及的分子和细胞途径。在本文中,我们开发了第一个结合了Hodgkin-Huxley型尖峰动力学的计算框架，动态离子浓度和谷氨酸稳态，神经元和星形胶质体积的变化，和离子交换与脉管系统成一个综合模型，以阐明谷氨酸摄取在扩散去极化（SD）的动力学中的作用-电生理事件是许多病理包括偏头痛的基础，缺血性卒中,动脉瘤性蛛网膜下腔出血,脑内血肿，和创伤。我们特别感兴趣的是研究谷氨酸在K灌注和氧葡萄糖剥夺引起的SD的持续时间和终止中的作用。我们的结果表明，谷氨酸信号在SD的动力学中起着关键作用，受损的谷氨酸摄取导致SD神经元恢复失败。我们通过实验证明，使用TFB-TBOA抑制星形细胞谷氨酸的摄取几乎使幼鼠视觉皮层切片2-3层中SD的持续时间延长了四倍，从而证实了模型的预测。模型方程要么纯粹是从电子中性的第一物理原理得出的，渗透,和粒子的守恒或这些原理和已知生理事实的组合。因此，我们声称我们的方法可以用作研究谷氨酸作用的未来指南，离子浓度，以及其他脑部病理和正常脑功能的动态细胞体积。
