Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
Neuron. 2019 Jun 5;102(5):1009-1024.e8. doi: 10.1016/j.neuron.2019.03.045. Epub 2019 Apr 29.
Maintaining average activity within a set-point range constitutes a fundamental property of central neural circuits. However, whether and how activity set points are regulated remains unknown. Integrating genome-scale metabolic modeling and experimental study of neuronal homeostasis, we identified mitochondrial dihydroorotate dehydrogenase (DHODH) as a regulator of activity set points in hippocampal networks. The DHODH inhibitor teriflunomide stably suppressed mean firing rates via synaptic and intrinsic excitability mechanisms by modulating mitochondrial Ca buffering and spare respiratory capacity. Bi-directional activity perturbations under DHODH blockade triggered firing rate compensation, while stabilizing firing to the lower level, indicating a change in the firing rate set point. In vivo, teriflunomide decreased CA3-CA1 synaptic transmission and CA1 mean firing rate and attenuated susceptibility to seizures, even in the intractable Dravet syndrome epilepsy model. Our results uncover mitochondria as a key regulator of activity set points, demonstrate the differential regulation of set points and compensatory mechanisms, and propose a new strategy to treat epilepsy.
维持设定点范围内的平均活动是中枢神经回路的基本特性。然而，活动设定点是否以及如何被调节尚不清楚。通过整合基因组规模的代谢建模和神经元动态平衡的实验研究，我们确定了线粒体二氢乳清酸脱氢酶（DHODH）是海马网络活动设定点的调节剂。DHODH 抑制剂特立氟胺通过调节线粒体 Ca 缓冲和备用呼吸能力，通过突触和内在兴奋性机制稳定地抑制平均放电率。DHODH 阻断下的双向活动扰动引发了放电率补偿，同时稳定到较低水平，表明放电率设定点发生了变化。在体内，特立氟胺降低 CA3-CA1 突触传递和 CA1 平均放电率，并减弱癫痫易感性，即使在难治性德拉维特综合征癫痫模型中也是如此。我们的研究结果揭示了线粒体作为活动设定点的关键调节剂，证明了设定点和补偿机制的差异调节，并提出了一种治疗癫痫的新策略。
