Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility.
Neuron
; 102(5): 1009-1024.e8, 2019 06 05.
Article
em En
| MEDLINE
| ID: mdl-31047779
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Convulsões
/
Sinapses
/
Toluidinas
/
Crotonatos
/
Cálcio
/
Epilepsias Mioclônicas
/
Transmissão Sináptica
/
Oxirredutases atuantes sobre Doadores de Grupo CH-CH
/
Hipocampo
/
Mitocôndrias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Neuron
Ano de publicação:
2019
Tipo de documento:
Article