Glial polyamine regulation of the neuronal-glial network

细胞外精胺（SPM）促进脑切片，并对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释放（在电去极化、缺血、胶质毒素期间）。这使我们认为内源性胶质SPM是 从去极化的神经胶质细胞释放到邻近的神经元，在那里它在调节神经元活动中起着至关重要的作用。我们的初步数据表明，SPM（i）选择性地阻断中间神经元上的快速谷氨酸受体（Ca 2+渗透性AMPA受体），（ii）从细胞外部位增强锥体细胞。因此，选择性阻断中间神经元与增强锥体细胞可能是SPM/胶质依赖性调节神经元网络的主要机制。我们的初步数据导致的新的假设，gUal神经元的关系是部分基于这些细胞之间的胞外多胺通量。我们的工作假设是积聚在神经胶质细胞中的SPM通过（i）非对抗的半间隙通道（半通道）从去极化的神经胶质细胞释放到神经元，并从（ii）神经元受体通道外起作用以调节神经元活性。具体地说，在神经元兴奋（和缺血）期间，[H+]o和[Ca 2 +] o的短暂下降连同[K+]o的增加将使神经胶质细胞退化，并促进内源性SPM的释放和作用。在较高浓度下，SPM可抑制各种谷氨酸受体，从而减少神经元通过AMPA和NMDA受体的Ca 2+内流，从而保护神经元免受Ca 2+损伤。神经胶质中SPM的缺失导致神经胶质K+-内向整流（Kir）通道的整流缓解， 这可以通过将过量的[K+] O从大脑转移到血管来额外保护神经元，血管是星形胶质细胞通过端足附着的“水槽”。因此，精胺是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累，可能是神经保护的基础。在这里我们要问：SPM是如何从神经胶质细胞中释放出来的，以及这种SPM是如何调节 整个大脑的神经网络这些问题将通过检查SPM通过半通道运输的机制，通过检查SPM对异源表达的Kir6.1/SUR 1和AMPAR的影响，并通过同时记录从中间神经元，星形胶质细胞和锥体细胞，同时确定半通道开放，SPM释放和神经元兴奋性改变之间的关系来解决。这些研究将 为理解神经胶质细胞在神经元活性调节中的新阐明的作用提供了一种新的机制。

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.