Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission
Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission
复制标题
DOI：
10.1073/pnas.1111098109
复制
发表时间：
2012-01-24
影响因子：
11.1
通讯作者：
Bessis, Alain
中科院分区：
文献类型：
--
作者：
Pascual, Olivier;Ben Achour, Sarrah;Bessis, Alain
神经元活动的精细控制对于快速适应环境的微妙变化至关重要。这种微调被认为是纯粹的神经元，直到发现星形胶质细胞是突触传递的活跃参与者。在成人海马体中，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。它们对环境的改变做出快速反应，并能够释放已知控制神经元功能和突触传递的分子。因此，小胶质细胞显示出突触伙伴的功能特征，但它们在突触传递调节中的参与尚未得到解决。我们将药理学方法与急性海马切片的电生理学分析和纯化细胞培养物中的 ATP 测定相结合，表明小胶质细胞的激活会诱导自发兴奋性突触后电流的快速增加。我们发现这种调节是通过 ATP 与星形胶质细胞上的 P2Y1R 结合介导的，并且不依赖于 TNF α 或 NOS2。我们的数据表明，小胶质细胞激活后会迅速释放少量 ATP，而星形胶质细胞反过来会放大这种释放。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者，并将小胶质细胞作为星形胶质细胞的上游伙伴。由于小胶质细胞的病理激活和神经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。
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 TNF alpha 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.