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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / drug effects
  • CA3 Region, Hippocampal / metabolism
  • Calcium / metabolism*
  • Crotonates / pharmacology*
  • Disease Models, Animal
  • Disease Susceptibility
  • Epilepsies, Myoclonic / metabolism*
  • Gene Knockdown Techniques
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Homeostasis
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Seizures / metabolism*
  • Synapses / drug effects*
  • Synapses / metabolism
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / genetics
  • Toluidines / pharmacology*

Substances

  • Crotonates
  • Toluidines
  • teriflunomide
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase
  • Calcium