Koizumi Schuichi, Fujishita Kayoko, Tsuda Makoto, Shigemoto-Mogami Yukari, Inoue Kazuhide
Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11023-8. doi: 10.1073/pnas.1834448100. Epub 2003 Sep 4.
Originally ascribed passive roles in the CNS, astrocytes are now known to have an active role in the regulation of synaptic transmission. Neuronal activity can evoke Ca2+ transients in astrocytes, and Ca2+ transients in astrocytes can evoke changes in neuronal activity. The excitatory neurotransmitter glutamate has been shown to mediate such bidirectional communication between astrocytes and neurons. We demonstrate here that ATP, a primary mediator of intercellular Ca2+ signaling among astrocytes, also mediates intercellular signaling between astrocytes and neurons in hippocampal cultures. Mechanical stimulation of astrocytes evoked Ca2+ waves mediated by the release of ATP and the activation of P2 receptors. Mechanically evoked Ca2+ waves led to decreased excitatory glutamatergic synaptic transmission in an ATP-dependent manner. Exogenous application of ATP does not affect postsynaptic glutamatergic responses but decreased presynaptic exocytotic events. Finally, we show that astrocytes exhibit spontaneous Ca2+ waves mediated by extracellular ATP and that inhibition of these Ca2+ responses enhanced excitatory glutamatergic transmission. We therefore conclude that ATP released from astrocytes exerts tonic and activity-dependent down-regulation of synaptic transmission via presynaptic mechanisms.
星形胶质细胞最初被认为在中枢神经系统中起被动作用，现在已知它们在调节突触传递中发挥积极作用。神经元活动可引发星形胶质细胞中的Ca2+瞬变，而星形胶质细胞中的Ca2+瞬变可引发神经元活动的变化。兴奋性神经递质谷氨酸已被证明可介导星形胶质细胞与神经元之间的这种双向通信。我们在此证明，ATP作为星形胶质细胞间细胞内Ca2+信号传导的主要介质，也介导海马培养物中星形胶质细胞与神经元之间的细胞间信号传导。对星形胶质细胞的机械刺激引发了由ATP释放和P2受体激活介导的Ca2+波。机械诱发的Ca2+波以ATP依赖的方式导致兴奋性谷氨酸能突触传递减少。外源性应用ATP不影响突触后谷氨酸能反应，但减少突触前胞吐事件。最后，我们表明星形胶质细胞表现出由细胞外ATP介导的自发Ca2+波，并且抑制这些Ca2+反应增强了兴奋性谷氨酸能传递。因此，我们得出结论，星形胶质细胞释放的ATP通过突触前机制对突触传递发挥张力性和活性依赖性下调作用。
