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

• DOI: 10.1016/j.neuron.2019.03.045
• Publication Date: 2019-04-29T10:47:33Z
• Authors: Boaz Styr; Nir Gonen; Daniel Zarhin; Antonella Ruggiero; Refaela Atsmon; Neta Gazit; Gabriella Braun; Samuel Frere; Irena Vertkin; Ilana Shapira; Michal Harel; Leore R. Heim; Maxim Katsenelson; Ohad Rechnitz; Saja Fadila; Dori Derdikman; Moran Rubinstein; Tamar Geiger; Eytan Ruppin; Inna Slutsky
• Keywords: Oxidoreductases Acting on CH-CH Group Donors; 0303 health sciences; Dihydroorotate Dehydrogenase; Hydroxybutyrates; Epilepsies, Myoclonic; CA3 Region, Hippocampal; Hippocampus; Synaptic Transmission; Article; Mitochondria; Disease Models, Animal; Mice; 03 medical and health sciences; Seizures; Crotonates; Gene Knockdown Techniques; Nitriles; Synapses; Animals; Homeostasis; Calcium; Disease Susceptibility; CA1 Region, Hippocampal

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.