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.

细胞外精子（SPM）促进了脑切片，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主要存储在星形胶质细胞（在电去极化期间，缺血，胶质素毒素）期间释放。这使我们提出内源性神经胶质spm是 从去极化的神经胶质到邻近的神经元中释放在调节神经元活性中起着至关重要的作用。我们的初步数据表明，SPM（i）有选择地阻止中间神经元上的快速谷氨酸受体（Ca2+可渗透AMPA受体），（ii）（ii）增强细胞外部位的锥体细胞。因此，选择性封锁中间神经元以及锥体细胞的增强可能是SPM/Glia依赖性神经元网络调节的主要机制。我们的初步数据导致了新的假设，即同时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，积累在神经胶质细胞中的SPM通过（i）从去极化吉拉到神经元到神经元的（ii）在神经元受体通道外的（II）起作用的（ii）通过（II）起作用神经元受体通道到调节神经元活性的（II）的作用。具体而言，在神经元激发（和缺血）期间，[H+] O和[Ca2+] otogeTher的短暂降低会随[K+] O的增加将去极化，并促进内源性SPM的释放和效果。在较高的浓度下，SPM降低了各种谷氨酸受体，从而通过AMPA和NMDA受体降低了神经元Ca 2+进入，这可能保护神经元免受CA2+损伤的影响。神经胶质中SPM的丧失会导致缓解神经胶质K+的整流（KIR）通道， 这可能会通过将多余的[K+]脑大脑移至血管，即由Endfeet附着的“下沉”来保护神经元。因此，精子是神经胶质与神经元之间的主要联系之一，如果有效地积聚在神经胶质中，则可能是神经保护的基础。在这里我们问：SPM如何从GLIA中释放，SPM如何调节 整个大脑的神经元网络？通过检查SPM对异源表达的KIR6.1/SUR1和AMPAR的影响，以及同时记录中间神经元，星形胶质细胞和金字塔细胞的同时记录，通过检查SPM对异源表达的KIR6.1/SUR1和AMPAR的作用，可以通过检查SPM传输的机制来解决这些问题。这些研究会 提供了一种新的机制，可以理解神经胶质细胞在调节神经元活性中的新作用。