論文 - 詳細
| RRC ID | 68623 |
|---|---|
| 著者 | Jeong J, Lee J, Kim JH, Lim C. |
| タイトル | Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset. |
| ジャーナル | PLoS Genet |
| 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. |
| 巻・号 | 17(10) |
| ページ | e1009871 |
| 公開日 | 2021-10-1 |
| DOI | 10.1371/journal.pgen.1009871 |
| PII | PGENETICS-D-21-00356 |
| PMID | 34714823 |
| PMC | PMC8555787 |
| MeSH | Animals Citric Acid / metabolism Citric Acid Cycle / genetics Citric Acid Cycle / physiology* Dicarboxylic Acid Transporters / genetics Dicarboxylic Acid Transporters / metabolism Drosophila / genetics Drosophila / metabolism Drosophila Proteins / genetics Drosophila Proteins / metabolism Glutamic Acid / genetics Glutamic Acid / metabolism* Male Metabolic Networks and Pathways / genetics Metabolic Networks and Pathways / physiology Mutation / genetics Neurons / metabolism Seizures / genetics Seizures / metabolism* Symporters / genetics Symporters / metabolism |
| IF | 5.175 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ショウジョウバエ | 3979R-1 3979R-3 12233R-3 6439R-2 5028R-2 |