A neuronal lactate uptake inhibitor slows recovery of extracellular ion concentration changes in the hippocampal CA3 region by affecting energy metabolism
A neuronal lactate uptake inhibitor slows recovery of extracellular ion concentration changes in the hippocampal CA3 region by affecting energy metabolism
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DOI：
10.1152/jn.00327.2016
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发表时间：
2016-11-01
影响因子：
2.5
通讯作者：
Heinemann, Uwe
中科院分区：
文献类型：
--
作者：
Angamo, Eskedar Ayele;Roesner, Joerg;Heinemann, Uwe
星形胶质细胞衍生的乳酸支持病理性增强的神经元代谢，但其在生理条件下的作用仍然存在争议。在这里，我们确定了星形细胞神经元乳酸穿梭对维持离子稳态和能量代谢的贡献。我们测试了 α-氰基-4-羟基肉桂酸 (4-CIN) 对诱发电位、刺激诱导的 K+、Na-+、Na-Ca2+ 和氧浓度变化以及海马区 CA3 黄素腺嘌呤二核苷酸 (FAD) 自发荧光变化的影响，该酸可通过阻断单羧酸转运蛋白 2 (MCT2) 介导的神经元乳酸摄取来干扰能量代谢。 4-CIN 阻断 MCT2 会减少突触诱发，但不会减少逆向群体峰值。这种效应依赖于 K-ATP 通道的激活，表明神经元 ATP 合成减少。相比之下，3,5-二羟基苯甲酸 (3,5-DHBA) 激活乳酸受体导致逆向和顺向群体峰值增加，表明 4-CIN 效应不是由乳酸积累和随后的乳酸受体激活介导的。所有离子瞬变的恢复动力学均延长，且基线 K+ 浓度因乳酸吸收的阻断而升高。乳酸有助于氧化代谢，因为基线呼吸和刺激引起的 PO2 变化均减少，而 FAD 荧光增加可能是由于 FAD 向 FADH 的转化减少(2)。这些数据表明，即使在存在充足葡萄糖的情况下，乳酸穿梭也有助于离子稳态和突触信号传导的调节。
Astrocyte-derived lactate supports pathologically enhanced neuronal metabolism, but its role under physiological conditions is still a matter of debate. Here, we determined the contribution of astrocytic neuronal lactate shuttle for maintenance of ion homeostasis and energy metabolism. We tested for the effects of alpha-cyano-4-hydroxycinnamic acid (4-CIN), which could interfere with energy metabolism by blocking monocarboxylate-transporter 2 ( MCT2)-mediated neuronal lactate uptake, on evoked potentials, stimulus-induced changes in K+, Na-+,Na- Ca2+, and oxygen concentrations as well as on changes in flavin adenine dinucleotide ( FAD) autofluorescence in the hippocampal area CA3. MCT2 blockade by 4-CIN reduced synaptically evoked but not antidromic population spikes. This effect was dependent on the activation of K-ATP channels indicating reduced neuronal ATP synthesis. By contrast, lactate receptor activation by 3,5-dihydroxybenzoic acid ( 3,5-DHBA) resulted in increased antidromic and orthodromic population spikes suggesting that 4-CIN effects are not mediated by lactate accumulation and subsequent activation of lactate receptors. Recovery kinetics of all ion transients were prolonged and baseline K+ concentration became elevated by blockade of lactate uptake. Lactate contributed to oxidative metabolism as both baseline respiration and stimulus-induced changes in PO2 were decreased, while FAD fluorescence increased likely due to a reduced conversion of FAD into FADH(2). These data suggest that lactate shuttle contributes to regulation of ion homeostatsis and synaptic signaling even in the presence of ample glucose.