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Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.

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.

SUBMITTER: Jeong J

PROVIDER: S-EPMC8555787 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.

Jeong Jiwon J Lee Jongbin J Kim Ji-Hyung JH Lim Chunghun C

PLoS genetics 20211029 10

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 citri ...[more]

PMID: 34714823

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Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.

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Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.

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