Bas-Orth Carlos, Tan Yan-Wei, Lau David, Bading Hilmar
From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany.
From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
J Biol Chem. 2017 Mar 31;292(13):5183-5194. doi: 10.1074/jbc.M116.761106. Epub 2017 Feb 14.
Synaptic activity drives changes in gene expression to promote long lasting adaptations of neuronal structure and function. One example of such an adaptive response is the buildup of acquired neuroprotection, a synaptic activity- and gene transcription-mediated increase in the resistance of neurons against harmful conditions. A hallmark of acquired neuroprotection is the stabilization of mitochondrial structure and function. We therefore re-examined previously identified sets of synaptic activity-regulated genes to identify genes that are directly linked to mitochondrial function. In mouse and rat primary hippocampal cultures, synaptic activity caused an up-regulation of glycolytic genes and a concomitant down-regulation of genes required for oxidative phosphorylation, mitochondrial biogenesis, and maintenance. Changes in metabolic gene expression were induced by action potential bursting, but not by glutamate bath application activating extrasynaptic NMDA receptors. The specific and coordinate pattern of gene expression changes suggested that synaptic activity promotes a shift of neuronal energy metabolism from oxidative phosphorylation toward aerobic glycolysis, also known as the Warburg effect. The ability of neurons to up-regulate glycolysis has, however, been debated. We therefore used FACS sorting to show that, in mixed neuron glia co-cultures, activity-dependent regulation of metabolic gene expression occurred in neurons. Changes in gene expression were accompanied by changes in the phosphorylation-dependent regulation of the key metabolic enzyme, pyruvate dehydrogenase. Finally, increased synaptic activity caused an increase in the ratio of l-lactate production to oxygen consumption in primary hippocampal cultures. Based on these data we suggest the existence of a synaptic activity-mediated neuronal Warburg effect that may promote mitochondrial homeostasis and neuroprotection.
突触活动驱动基因表达的变化，以促进神经元结构和功能的长期适应性改变。这种适应性反应的一个例子是获得性神经保护的建立，这是一种由突触活动和基因转录介导的神经元对有害条件抵抗力的增加。获得性神经保护的一个标志是线粒体结构和功能的稳定。因此，我们重新审视了先前确定的突触活动调节基因集，以确定与线粒体功能直接相关的基因。在小鼠和大鼠原代海马培养物中，突触活动导致糖酵解基因上调，同时氧化磷酸化、线粒体生物发生和维持所需的基因下调。代谢基因表达的变化是由动作电位爆发诱导的，而不是由激活突触外NMDA受体的谷氨酸浴应用诱导的。基因表达变化的特定和协调模式表明，突触活动促进神经元能量代谢从氧化磷酸化向有氧糖酵解的转变，也称为瓦尔堡效应。然而，神经元上调糖酵解的能力一直存在争议。因此，我们使用荧光激活细胞分选术表明，在混合神经元-胶质细胞共培养物中，代谢基因表达的活动依赖性调节发生在神经元中。基因表达的变化伴随着关键代谢酶丙酮酸脱氢酶的磷酸化依赖性调节的变化。最后，增加的突触活动导致原代海马培养物中l-乳酸产生与氧气消耗的比率增加。基于这些数据，我们认为存在一种突触活动介导的神经元瓦尔堡效应，它可能促进线粒体稳态和神经保护。
