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

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 m...

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Published in:Neuron (Cambridge, Mass.) Mass.), 2019-06, Vol.102 (5), p.1009-1024.e8
Main Authors: Styr, Boaz, Gonen, Nir, Zarhin, Daniel, Ruggiero, Antonella, Atsmon, Refaela, Gazit, Neta, Braun, Gabriella, Frere, Samuel, Vertkin, Irena, Shapira, Ilana, Harel, Michal, Heim, Leore R., Katsenelson, Maxim, Rechnitz, Ohad, Fadila, Saja, Derdikman, Dori, Rubinstein, Moran, Geiger, Tamar, Ruppin, Eytan, Slutsky, Inna
Format: Article
Language:English
Subjects:
Animals
CA1 Region, Hippocampal - drug effects
CA1 Region, Hippocampal - metabolism
CA3 Region, Hippocampal - drug effects
CA3 Region, Hippocampal - metabolism
calcium
Calcium (mitochondrial)
Calcium - metabolism
Calcium buffering
Convulsions & seizures
Crotonates - pharmacology
Dihydroorotate dehydrogenase
Disease Models, Animal
Disease Susceptibility
Dravet syndrome
Enzymes
Epilepsies, Myoclonic - metabolism
Epilepsy
Excitability
Firing rate
Gene Knockdown Techniques
Genomes
Hippocampus
Hippocampus - drug effects
Hippocampus - metabolism
Homeostasis
Metabolism
Mice
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Neural networks
neuronal metabolism
Neurosciences
Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors
Oxidoreductases Acting on CH-CH Group Donors - genetics
Physiology
Seizures
Seizures - metabolism
set point
Statistical analysis
Synapses - drug effects
Synapses - metabolism
Synaptic transmission
Synaptic Transmission - drug effects
Synaptic Transmission - genetics
Toluidines - pharmacology
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Summary: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. [Display omitted] •Inhibition of mitochondrial DHODH stably decreases mean firing rate set point•DHODH regulates mitochondrial Ca2+ buffering and spare respiratory capacity•Homeostatic responses to activity perturbations are maintained under DHODH blockade•DHODH inhibition reduces susceptibility to seizures in intractable epilepsy model Firing rate set-point regulation has puzzled researchers for decades. Our findings show that mitochondrial DHODH meets the criteria of a bone fide regulator of activity set points and suggest lowering firing set point as a new strategy to treat epilepsy.
ISSN:0896-6273
1097-4199
1097-4199
DOI:10.1016/j.neuron.2019.03.045