Glial polyamine regulation of the neuronal-glial network

神经胶质网络的胶质多胺调节

• 批准号: 7120462
• 负责人: SERGUEI N SKATCHKOV
• 金额: $ 26.9万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-07 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120462
• 关键词: AMPA receptors; RNA interference; Xenopus; Xenopus oocyte; astrocytes; calcium flux; cell cell interaction; glia; hippocampus; ion channel blocker; laboratory rat; membrane channels; neural transmission; neurons; neuroprotectants; potassium channel; protein kinase C; receptor expression; spermine; tissue /cell culture; voltage /patch clamp

Extracellular spermine (SPM) facilitates brain slices and is neuroprotective against NMDA-induced neurotoxicity. Intriguingly, we have found that the polyamine SPM in the hippocampus is stored predominantly in and is released from astrocytes (during electrical depolarization, ischemia, gliotoxin). This leads us to suggest that endogenous glial SPM is released from depolarized glia to neighboring neurons where it plays a crucial role in regulating neuronal activity. Our preliminary data show that SPM (i) selectively blocks fast glutamate receptors (Ca2+-permeable AMPA receptors) on interneurons and (ii) potentiates pyramidal cells from extracellular sites. Therefore, selective blockade of interneurons together with potentiation of pyramidal cells may be a major mechanism for SPM/glia-dependent regulation of the neuronal network. Our preliminary data lead to the novel hypothesis that the gUal-neuronal relationship is based in part by extracellular polyamine fluxes between these cells. Our working hypothesis is that SPM accumulated in glial cells is released via (i) unopposed hemi-gap channels (hemichannels) from depolarized gila to neurons and acts from (ii) outside the neuronal receptor-channels to modulate neuronal activity. Specifically, during neuronal excitation (and ischemia) a transient fall of [H+]o and [Ca2+]otogether with increased [K+]o will depolarize glia and facilitate both the release and the effect of endogenous SPM. At higher concentrations, SPM depresses all kinds of glutamate receptors, resulting in a decrease of neuronal Ca 2+ entry through AMPA and NMDA receptors which may protect neurons against Ca2+-damage. Loss of SPM in glia leads to relief of rectification of glial K+-inwardly rectifying (Kir) channels, this may additionally protect neurons by removing excess [K+]ofrom brain to blood vessels, the "sinks" to which astrocytes are attached by endfeet. Thus, spermine is one of the major links between glia and neurons and if efficiently accumulated in glia, may be a basis of neuroprotection. Here we ask: how is SPM released from glia and how does this SPM regulate the neuronal network in whole brain? These questions will be addressed by examining the mechanism of SPM transport through hemichannels, by examining the effect of SPM on heterologously expressed Kir6.1/SUR1 and AMPARs and by simultaneous recording from interneurons, astrocytes and pyramidal cells while determining the relationship between opening of hemichannels, SPM release and alterations in neuronal excitability. These studies will provide a novel mechanism for understanding the newly elucidated role of glial cells in the regulation of neuronal activity.

细胞外精胺(SPM)促进脑片的生长，对NMDA诱导的神经毒性具有神经保护作用。有趣的是，我们发现海马区的多胺SPM主要储存在星形胶质细胞中，并从星形胶质细胞释放(在电去极化、缺血、神经胶质毒素期间)。这导致我们认为内源性胶质细胞SPM是 从去极化的胶质细胞释放到邻近的神经元，在调节神经元活动方面发挥关键作用。我们的初步数据显示，SPM(I)选择性地阻断中间神经元上的快速谷氨酸受体(钙离子通透性AMPA受体)，以及(II)加强细胞外部位的锥体细胞。因此，选择性阻断中间神经元和增强锥体细胞可能是SPM/胶质细胞依赖的神经元网络调节的主要机制。我们的初步数据导致了一个新的假设，即Gual-神经元关系部分地基于这些细胞之间的胞外多胺流量。我们的工作假设是，神经胶质细胞中积累的SPM通过(I)非相对的半缝隙通道(半通道)从去极化的GILA释放到神经元，并从(Ii)神经元受体通道外作用于调节神经元的活动。具体地说，在神经元兴奋(和缺血)过程中，[H+]o和[Ca2+]o的短暂下降以及[K+]o的升高将使胶质细胞去极化，从而促进内源性SPM的释放和作用。在较高浓度时，SPM抑制各种谷氨酸受体，通过AMPA和NMDA受体减少神经元内钙内流，从而保护神经元免受钙损伤。胶质细胞中SPM的丢失导致神经胶质K+-内向整流(KIR)通道的整流缓解， 这可能通过清除从大脑到血管的多余的[K+]来额外保护神经元，血管是星形胶质细胞通过末端脚连接到的“槽”。因此，精胺是神经胶质细胞和神经元之间的主要联系之一，如果在胶质细胞中有效积聚，可能是神经保护的基础。在这里，我们问：SPM是如何从胶质细胞中释放出来的，这种SPM是如何调节的 整个大脑中的神经网络？这些问题将通过研究SPM通过半槽转运的机制，通过检测SPM对Kir6.1/SUR1和AMPAR异源表达的影响，以及通过同时记录中间神经元、星形胶质细胞和锥体细胞来解决，同时确定半槽开放、SPM释放和神经元兴奋性变化之间的关系。这些研究将 为理解最近阐明的神经胶质细胞在神经元活动调节中的作用提供了新的机制。