Liu Qing-song, Xu Qiwu, Arcuino Gregory, Kang Jian, Nedergaard Maiken
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3172-7. doi: 10.1073/pnas.0306731101. Epub 2004 Feb 6.
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 Ca(2+)-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 Ca(2+) in astrocytes, induced by uncaging Ca(2+), 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 Ca(2+) elevation in astrocytes. Kainate receptors containing the GluR5 subunit seemed to mediate the observed effect because a selective GluR5-containing kainate receptor antagonist blocked the changes in sIPSCs induced by Ca(2+) uncaging, and bath application of a selective GluR5-containing receptor agonist robustly potentiated sIPSCs. When tetrodotoxin was included to block action potentials, Ca(2+) 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.
外源性海人酸受体激动剂已被证明可调节海马体中的抑制性突触传递，但受体生理激活所涉及的途径仍 largely 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体中间神经元上的海人酸受体这一假设。我们在此报告，通过 Ca(2+) 解笼、邻硝基苯 - EGTA 诱导的星形胶质细胞内 Ca(2+) 升高，增加了大鼠海马体切片中附近中间神经元的动作电位驱动的自发抑制性突触后电流。这种效应被 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/海人酸谷氨酸受体拮抗剂阻断，但未被选择性 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，在星形胶质细胞 Ca(2+) 升高期间海人酸受体被激活。含有 GluR5 亚基的海人酸受体似乎介导了观察到的效应，因为选择性含 GluR5 的海人酸受体拮抗剂阻断了 Ca(2+) 解笼诱导的 sIPSCs 变化，并且浴用选择性含 GluR5 的受体激动剂强烈增强了 sIPSCs。当加入河豚毒素以阻断动作电位时，Ca(2+) 解笼诱导微小抑制性突触后电流频率小幅下降，这不受 AMPA/海人酸受体拮抗剂影响。我们的数据表明，星形胶质细胞衍生的非突触性谷氨酸源代表了一种可激活神经元海人酸受体的信号通路。通过调节中间神经元的活动，星形胶质细胞可能在海马体的回路功能中起关键作用。
