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) 有助于脑切片，并且对 NMDA 诱导的神经毒性具有神经保护作用。有趣的是，我们发现海马中的多胺 SPM 主要储存在星形胶质细胞中并从星形胶质细胞中释放（在电去极化、缺血、胶质毒素期间）。这使我们认为内源性神经胶质 SPM 是 从去极化的神经胶质细胞释放到邻近的神经元，在调节神经元活动中发挥着至关重要的作用。我们的初步数据表明，SPM (i) 选择性阻断中间神经元上的快速谷氨酸受体（Ca2+ 通透性 AMPA 受体），以及 (ii) 从细胞外位点增强锥体细胞。因此，选择性阻断中间神经元和锥体细胞的增强可能是 SPM/神经胶质细胞依赖性神经网络调节的主要机制。我们的初步数据得出了一个新的假设，即胶质神经元关系部分基于这些细胞之间的细胞外多胺通量。我们的工作假设是，神经胶质细胞中积累的 SPM 通过 (i) 从去极化吉拉到神经元的无对抗半间隙通道（半通道）释放，并从 (ii) 神经元受体通道外部发挥作用，以调节神经元活动。具体来说，在神经元兴奋（和缺血）期间，[H+]o 和 [Ca2+]o 的短暂下降以及 [K+]o 的增加将使神经胶质细胞去极化，并促进内源性 SPM 的释放和作用。在较高浓度下，SPM 会抑制各种谷氨酸受体，导致神经元 Ca 2+ 通过 AMPA 和 NMDA 受体的进入减少，这可能会保护神经元免受 Ca2+ 损伤。神经胶质细胞中 SPM 的损失会导致神经胶质细胞 K+ 内向整流 (Kir) 通道的整流减轻， 这还可以通过将多余的[K+]从大脑转移到血管（星形胶质细胞通过末端附着的“下沉”）来额外保护神经元。因此，精胺是神经胶质细胞和神经元之间的主要联系之一，如果在神经胶质细胞中有效积累，则可能成为神经保护的基础。这里我们问：SPM是如何从胶质细胞中释放出来的，这个SPM是如何调节的 全脑的神经元网络？这些问题将通过检查半通道的 SPM 运输机制、检查 SPM 对异源表达的 Kir6.1/SUR1 和 AMPAR 的影响以及通过中间神经元、星形胶质细胞和锥体细胞的同步记录来解决，同时确定半通道开放之间的关系、SPM 释放和神经元兴奋性的改变。这些研究将 为理解神经胶质细胞在神经元活动调节中新阐明的作用提供了一种新的机制。