Sotelo-Hitschfeld Tamara, Niemeyer María I, Mächler Philipp, Ruminot Iván, Lerchundi Rodrigo, Wyss Matthias T, Stobart Jillian, Fernández-Moncada Ignacio, Valdebenito Rocío, Garrido-Gerter Pamela, Contreras-Baeza Yasna, Schneider Bernard L, Aebischer Patrick, Lengacher Sylvain, San Martín Alejandro, Le Douce Juliette, Bonvento Gilles, Magistretti Pierre J, Sepúlveda Francisco V, Weber Bruno, Barros L Felipe
Centro de Estudios Científicos, Valdivia 5110466, Chile, Universidad Austral de Chile, Valdivia, Chile.
Centro de Estudios Científicos, Valdivia 5110466, Chile.
J Neurosci. 2015 Mar 11;35(10):4168-78. doi: 10.1523/JNEUROSCI.5036-14.2015.
Excitatory synaptic transmission is accompanied by a local surge in interstitial lactate that occurs despite adequate oxygen availability, a puzzling phenomenon termed aerobic glycolysis. In addition to its role as an energy substrate, recent studies have shown that lactate modulates neuronal excitability acting through various targets, including NMDA receptors and G-protein-coupled receptors specific for lactate, but little is known about the cellular and molecular mechanisms responsible for the increase in interstitial lactate. Using a panel of genetically encoded fluorescence nanosensors for energy metabolites, we show here that mouse astrocytes in culture, in cortical slices, and in vivo maintain a steady-state reservoir of lactate. The reservoir was released to the extracellular space immediately after exposure of astrocytes to a physiological rise in extracellular K(+) or cell depolarization. Cell-attached patch-clamp analysis of cultured astrocytes revealed a 37 pS lactate-permeable ion channel activated by cell depolarization. The channel was modulated by lactate itself, resulting in a positive feedback loop for lactate release. A rapid fall in intracellular lactate levels was also observed in cortical astrocytes of anesthetized mice in response to local field stimulation. The existence of an astrocytic lactate reservoir and its quick mobilization via an ion channel in response to a neuronal cue provides fresh support to lactate roles in neuronal fueling and in gliotransmission.
兴奋性突触传递伴随着细胞外间隙乳酸的局部激增，尽管有充足的氧气供应，这种令人费解的现象被称为有氧糖酵解。除了作为能量底物的作用外，最近的研究表明，乳酸通过各种靶点调节神经元兴奋性，包括NMDA受体和乳酸特异性的G蛋白偶联受体，但对于细胞外间隙乳酸增加的细胞和分子机制知之甚少。使用一组用于能量代谢物的基因编码荧光纳米传感器，我们在此表明，培养的、皮质切片中的以及体内的小鼠星形胶质细胞维持着一个乳酸的稳态储存库。在星形胶质细胞暴露于细胞外K(+)的生理性升高或细胞去极化后，该储存库立即释放到细胞外空间。对培养的星形胶质细胞进行细胞贴附式膜片钳分析发现，一个37 pS的乳酸通透离子通道被细胞去极化激活。该通道受乳酸自身调节，导致乳酸释放的正反馈回路。在麻醉小鼠的皮质星形胶质细胞中，响应局部场刺激也观察到细胞内乳酸水平迅速下降。星形胶质细胞乳酸储存库的存在及其通过离子通道对神经元信号的快速动员，为乳酸在神经元供能和胶质递质传递中的作用提供了新的支持。
