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小胶质细胞激活触发星形胶质细胞介导的兴奋性神经递质传递的调制。

Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission.

机构信息

Institut de Biologie de l'Ecole Normale Supérieure, F-75005 Paris, France.

出版信息

Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):E197-205. doi: 10.1073/pnas.1111098109. Epub 2011 Dec 13.

DOI:10.1073/pnas.1111098109
PMID:22167804
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3268269/
Abstract

Fine control of neuronal activity is crucial to rapidly adjust to subtle changes of the environment. This fine tuning was thought to be purely neuronal until the discovery that astrocytes are active players of synaptic transmission. In the adult hippocampus, microglia are the other major glial cell type. Microglia are highly dynamic and closely associated with neurons and astrocytes. They react rapidly to modifications of their environment and are able to release molecules known to control neuronal function and synaptic transmission. Therefore, microglia display functional features of synaptic partners, but their involvement in the regulation of synaptic transmission has not yet been addressed. We have used a combination of pharmacological approaches with electrophysiological analysis on acute hippocampal slices and ATP assays in purified cell cultures to show that activation of microglia induces a rapid increase of spontaneous excitatory postsynaptic currents. We found that this modulation is mediated by binding of ATP to P2Y1R located on astrocytes and is independent of TNFα or NOS2. Our data indicate that, on activation, microglia cells rapidly release small amounts of ATP, and astrocytes, in turn, amplified this release. Finally, P2Y1 stimulation of astrocytes increased excitatory postsynaptic current frequency through a metabotropic glutamate receptor 5-dependent mechanism. These results indicate that microglia are genuine regulators of neurotransmission and place microglia as upstream partners of astrocytes. Because pathological activation of microglia and alteration of neurotransmission are two early symptoms of most brain diseases, our work also provides a basis for understanding synaptic dysfunction in neuronal diseases.

摘要

精细控制神经元活动对于快速适应环境的微妙变化至关重要。直到发现星形胶质细胞是突触传递的活跃参与者,这种微调才被认为纯粹是神经元的。在成年海马体中,小胶质细胞是另一种主要的神经胶质细胞类型。小胶质细胞高度动态,与神经元和星形胶质细胞密切相关。它们对环境的变化迅速做出反应,并能够释放已知控制神经元功能和突触传递的分子。因此,小胶质细胞表现出突触伙伴的功能特征,但它们在调节突触传递中的作用尚未得到解决。我们使用药理学方法结合急性海马切片的电生理分析和纯化细胞培养物中的 ATP 测定,表明小胶质细胞的激活诱导自发性兴奋性突触后电流的快速增加。我们发现这种调制是通过位于星形胶质细胞上的 P2Y1R 与 ATP 结合介导的,并且与 TNFα 或 NOS2 无关。我们的数据表明,在激活时,小胶质细胞细胞迅速释放少量 ATP,而星形胶质细胞反过来放大了这种释放。最后,P2Y1 刺激星形胶质细胞通过代谢型谷氨酸受体 5 依赖性机制增加兴奋性突触后电流频率。这些结果表明小胶质细胞是神经传递的真正调节剂,并将小胶质细胞置于星形胶质细胞的上游伙伴位置。由于小胶质细胞的病理性激活和神经递质传递的改变是大多数脑部疾病的两个早期症状,因此我们的工作也为理解神经元疾病中的突触功能障碍提供了基础。

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Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity.星形胶质细胞自发释放的谷氨酸为突触可塑性设定了阈值。
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