Format

Send to

Choose Destination
Neuron. 2019 Jun 5;102(5):1009-1024.e8. doi: 10.1016/j.neuron.2019.03.045. Epub 2019 Apr 29.

Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility.

Author information

1
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
2
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.
3
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
4
Department of Neuroscience, Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, 31096 Haifa, Israel.
5
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; The Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
6
Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel; Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; The Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
7
Cancer Data Science Lab (CDSL), National Cancer Institute, NIH, Bethesda, MD, USA.
8
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. Electronic address: islutsky@tauex.tau.ac.il.

Abstract

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 Ca2+ 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.

KEYWORDS:

Dravet syndrome; calcium; dihydroorotate dehydrogenase; epilepsy; firing rate; hippocampus; homeostasis; mitochondria; neuronal metabolism; set point

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center