Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
PLoS Genet
; 17(10): e1009871, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-34714823
ABSTRACT
Kohlschütter-Tönz syndrome (KTS) manifests as neurological dysfunctions, including early-onset seizures. Mutations in the citrate transporter SLC13A5 are associated with KTS, yet their underlying mechanisms remain elusive. Here, we report that a Drosophila SLC13A5 homolog, I'm not dead yet (Indy), constitutes a neurometabolic pathway that suppresses seizure. Loss of Indy function in glutamatergic neurons caused "bang-induced" seizure-like behaviors. In fact, glutamate biosynthesis from the citric acid cycle was limiting in Indy mutants for seizure-suppressing glutamate transmission. Oral administration of the rate-limiting α-ketoglutarate in the metabolic pathway rescued low glutamate levels in Indy mutants and ameliorated their seizure-like behaviors. This metabolic control of the seizure susceptibility was mapped to a pair of glutamatergic neurons, reversible by optogenetic controls of their activity, and further relayed onto fan-shaped body neurons via the ionotropic glutamate receptors. Accordingly, our findings reveal a micro-circuit that links neural metabolism to seizure, providing important clues to KTS-associated neurodevelopmental deficits.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Convulsões
/
Ciclo do Ácido Cítrico
/
Ácido Glutâmico
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article