Astrocyte-mediated activation of neuronal kainate receptors
Astrocyte-mediated activation of neuronal kainate receptors
复制标题
DOI：
10.1073/pnas.0306731101
复制
发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Nedergaard, M
中科院分区：
文献类型：
--
作者：
Liu, QS;Xu, QW;Nedergaard, M
外源性红藻氨酸受体激动剂已被证明可以调节海马中的抑制性突触传递，但参与受体生理激活的途径在很大程度上仍然未知。越来越多的证据表明，星形胶质细胞可以以Ca 2+依赖的方式释放谷氨酸，并向邻近的神经元发出信号。我们测试了星形胶质细胞衍生的谷氨酸激活海马中间神经元上的红藻氨酸受体的假设。我们在这里报告，在星形胶质细胞内钙离子的升高，诱导uncaging Ca 2+，o-nitrophenyl-EGTA，增加动作电位驱动的自发抑制性突触后电流在附近的大鼠海马脑片的中间神经元。这种作用被α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/红藻氨酸谷氨酸受体拮抗剂阻断，但不被选择性AMPA受体或N-甲基-D-天冬氨酸受体拮抗剂阻断。这种药理学特征表明，红藻氨酸受体在星形胶质细胞中的Ca 2+升高期间被激活。含有OURS亚基的红藻氨酸受体似乎介导了观察到的效果，因为选择性的含有GluR 5的红藻氨酸受体拮抗剂阻断了由Ca 2+释放诱导的sIPSC的变化，并且浴应用选择性的含有GluR 5的受体激动剂强烈地增强了sIPSC。当河豚毒素被包括在阻断动作电位，Ca 2 + uncaging诱导的小型抑制性突触后电流，这是不受AMPA/红藻氨酸受体拮抗剂的频率略有下降。我们的数据表明，星形胶质细胞衍生的，非突触来源的谷氨酸代表了一个信号通路，可以激活神经元红藻氨酸受体。星形胶质细胞可能通过调节中间神经元的活性，在海马神经回路功能中发挥重要作用。
Exogenous kainate receptor agonists have been shown to modulate inhibitory synaptic transmission in the hippocampus, but the pathways involved in physiological activation of the receptors remain largely unknown. Accumulating evidence indicates that astrocytes can release glutamate in a Ca2+-dependent manner and signal to neighboring neurons. We tested the hypothesis that astrocyte-derived glutamate activates kainate receptors on hippocampal interneurons. We report here that elevation of intracellular Ca2+ in astrocytes, induced by uncaging Ca2+, o-nitrophenyl-EGTA, increased action potential-driven spontaneous inhibitory postsynaptic currents in nearby interneurons in rat hippocampal slices. This effect was blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonists, but not by selective AMPA receptor or N-methyl-D-aspartate receptor antagonists. This pharmacological profile indicates that kainate receptors were activated during Ca2+ elevation in astrocytes. Kainate receptors containing the OURS subunit seemed to mediate the observed effect because a selective GluR5-containing kainate receptor antagonist blocked the changes in sIPSCs induced by Ca2+ uncaging, and bath application of a selective GluR5-containing receptor agonist robustly potentiated sIPSCs. When tetrodotoxin was included to block action potentials, Ca2+ uncaging induced a small decrease in the frequency of miniature inhibitory postsynaptic currents, which was not affected by AMPA/kainate receptor antagonists. Our data suggest that an astrocyte-derived, nonsynaptic source of glutamate represents a signaling pathway that can activate neuronal kainate receptors. By modulating the activity of interneurons, astrocytes may play a critical role in circuit function of hippocampus.