Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex.
Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex.
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DOI：
10.1371/journal.pbio.1001747
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发表时间：
2014-01
期刊：
影响因子：
9.8
通讯作者：
Pankratov Y
中科院分区：
文献类型：
--
作者：
Lalo U;Palygin O;Rasooli-Nejad S;Andrew J;Haydon PG;Pankratov Y
星形胶质细胞通过胞吐作用从突触样囊泡分泌ATP，激活神经元P2 X受体，这有助于突触后GABA受体下调，最终介导脑功能所需的星形胶质细胞和神经元之间的通信。神经元和神经胶质细胞之间的通信对于许多脑功能是重要的。星形胶质细胞可以通过Ca 2+刺激释放各种胶质递质（包括谷氨酸和ATP）来调节突触强度。星形胶质细胞释放ATP的生理作用通过其对神经胶质Ca 2+波的贡献以及对神经元活动和睡眠稳态的嘌呤能调节而被提出。神经胶质递质释放的机制仍不确定，胞吐作用是最有趣和有争议的途径。我们研究了ATP从急性解离的皮质星形胶质细胞释放使用“嗅细胞”的方法，并证明释放是囊泡的性质，可以通过代谢型和离子型受体或直接UV-uncaging细胞内Ca 2+的升高触发。新皮质星形胶质细胞的ATP胞吐作用发生在毫秒的时间尺度上，与最近在海马中报道的通过Best 1和TREK-1通道的胶质递质的非囊泡释放慢得多的时间尺度形成对比。此外，我们发现，皮质星形胶质细胞胞浆Ca 2+的升高触发ATP的释放，直接激活锥体神经元中的量子嘌呤能电流。神经胶质细胞驱动的嘌呤能电流的神经元的爆发，其次是突触和紧张性抑制显着衰减。通过神经元P2 X嘌呤受体的Ca 2+进入导致GABAA受体的磷酸化依赖性下调。突触后GABA受体的负性嘌呤能调制伴随着GABA释放的小突触前增强。当星形胶质细胞表达dn-SNARE以损害胞吐作用时，在神经元中未观察到胶质细胞驱动的抑制性传递的嘌呤能调制。星形胶质细胞驱动的嘌呤能电流和神经胶质细胞驱动的GABA受体的调制显着减少P2 X4基因敲除小鼠。我们的数据提供了一个关键的证据，以支持ATP从星形胶质细胞在新皮层的胞吐的生理重要性。脑功能取决于两种主要类型的细胞之间的相互作用：神经元传输电信号和神经胶质细胞，控制脑循环和神经元稳态。越来越多的证据表明，星形胶质细胞通过释放“胶质递质”（包括谷氨酸和ATP）参与调节神经元兴奋性和突触可塑性。研究表明，星形胶质细胞释放ATP的重要性，通过调节已知的“嘌呤能”受体，证明其对神经元活动和睡眠稳态的贡献。但是，神经胶质递质释放的机制和神经胶质与神经元直接通讯的生理意义仍然是未知的和激烈的争论。在这里，我们调查释放ATP从星形胶质细胞的大脑新皮层，并证明星形胶质细胞可以释放ATP的Ca 2+依赖的胞吐作用，最有可能从突触样微泡。我们还发现，囊泡释放的ATP从星形胶质细胞可以直接激活兴奋性信号在邻近的神经元，通过嘌呤能P2 X受体。我们看到，星形胶质细胞驱动的ATP激活这些P2 X受体下调了新皮层神经元中的抑制性突触信号。我们的研究结果表明，胞吐的胶质递质是重要的星形胶质细胞和神经元之间的通信在新皮层。
Astrocytes secrete ATP by exocytosis from synaptic-like vesicles, activating neuronal P2X receptors, which contribute to postsynaptic GABA receptor down-regulation, ultimately mediating the communication between astrocytes and neurons required for brain function. Communication between neuronal and glial cells is important for many brain functions. Astrocytes can modulate synaptic strength via Ca2+-stimulated release of various gliotransmitters, including glutamate and ATP. A physiological role of ATP release from astrocytes was suggested by its contribution to glial Ca2+-waves and purinergic modulation of neuronal activity and sleep homeostasis. The mechanisms underlying release of gliotransmitters remain uncertain, and exocytosis is the most intriguing and debated pathway. We investigated release of ATP from acutely dissociated cortical astrocytes using “sniff-cell” approach and demonstrated that release is vesicular in nature and can be triggered by elevation of intracellular Ca2+ via metabotropic and ionotropic receptors or direct UV-uncaging. The exocytosis of ATP from neocortical astrocytes occurred in the millisecond time scale contrasting with much slower nonvesicular release of gliotransmitters via Best1 and TREK-1 channels, reported recently in hippocampus. Furthermore, we discovered that elevation of cytosolic Ca2+ in cortical astrocytes triggered the release of ATP that directly activated quantal purinergic currents in the pyramidal neurons. The glia-driven burst of purinergic currents in neurons was followed by significant attenuation of both synaptic and tonic inhibition. The Ca2+-entry through the neuronal P2X purinoreceptors led to phosphorylation-dependent down-regulation of GABAA receptors. The negative purinergic modulation of postsynaptic GABA receptors was accompanied by small presynaptic enhancement of GABA release. Glia-driven purinergic modulation of inhibitory transmission was not observed in neurons when astrocytes expressed dn-SNARE to impair exocytosis. The astrocyte-driven purinergic currents and glia-driven modulation of GABA receptors were significantly reduced in the P2X4 KO mice. Our data provide a key evidence to support the physiological importance of exocytosis of ATP from astrocytes in the neocortex. Brain function depends on the interaction between two major types of cells: neurons transmitting electrical signals and glial cells, which control cerebral circulation and neuronal homeostasis. There is a growing evidence of the participation of astrocytes in regulating neuronal excitability and synaptic plasticity via the release of “gliotransmitters,” which include glutamate and ATP. The importance of ATP release from astrocytes was suggested by studies that demonstrated its contribution to neuronal activity and sleep homeostasis via modulation of known “purinergic” receptors. But the mechanisms underlying gliotransmitter release and the physiological significance of direct glia-to-neuron communication remain unknown and intensively debated. Here, we investigate the release of ATP from astrocytes of brain neocortex and demonstrate that astrocytes can release ATP by Ca2+-dependent exocytosis, most likely from synaptic-like microvesicles. We also find that vesicular release of ATP from astrocytes can directly activate excitatory signaling in the neighboring neurons, operating through purinergic P2X receptors. We saw that activation of these P2X receptors by astrocyte-driven ATP down-regulated the inhibitory synaptic signaling in the neocortical neurons. Our results imply that exocytosis of gliotransmitters is important for the communication between astrocytes and neurons in the neocortex.
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哺乳动物海马缺血期间 ATP 和腺苷释放的时间和机械解离。
影响因子：
4.7
作者：
Frenguelli BG;Wigmore G;Llaudet E;Dale N
通讯作者：
Dale N
DOI：
10.1126/science.1190721
发表时间：
2010-07-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gourine AV;Kasymov V;Marina N;Tang F;Figueiredo MF;Lane S;Teschemacher AG;Spyer KM;Deisseroth K;Kasparov S
通讯作者：
Kasparov S
影响因子：
5.5
作者：
Huckstepp, Robert T. R.;Bihi, Rachid Id;Dale, Nicholas
通讯作者：
Dale, Nicholas
影响因子：
3.8
作者：
Ding, SH;Sachs, F
通讯作者：
Sachs, F
影响因子：
64.8
作者：
通讯作者：
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