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

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 (Ind...

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Main Authors:	Jiwon Jeong, Jongbin Lee, Ji-Hyung Kim, Chunghun Lim
Format:	article
Language:	EN
Published:	Public Library of Science (PLoS) 2021
Subjects:	Genetics QH426-470
Online Access:	https://doaj.org/article/9a656d4d0f794afb8c5a3b195cb8b474
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spelling	oai:doaj.org-article:9a656d4d0f794afb8c5a3b195cb8b4742021-12-02T20:03:28ZMetabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.1553-73901553-740410.1371/journal.pgen.1009871https://doaj.org/article/9a656d4d0f794afb8c5a3b195cb8b4742021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009871https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Kohlschütter-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.Jiwon JeongJongbin LeeJi-Hyung KimChunghun LimPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 10, p e1009871 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Jiwon Jeong Jongbin Lee Ji-Hyung Kim Chunghun Lim Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
description	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.
format	article
author	Jiwon Jeong Jongbin Lee Ji-Hyung Kim Chunghun Lim
author_facet	Jiwon Jeong Jongbin Lee Ji-Hyung Kim Chunghun Lim
author_sort	Jiwon Jeong
title	Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
title_short	Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
title_full	Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
title_fullStr	Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
title_full_unstemmed	Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
title_sort	metabolic flux from the krebs cycle to glutamate transmission tunes a neural brake on seizure onset.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/9a656d4d0f794afb8c5a3b195cb8b474
work_keys_str_mv	AT jiwonjeong metabolicfluxfromthekrebscycletoglutamatetransmissiontunesaneuralbrakeonseizureonset AT jongbinlee metabolicfluxfromthekrebscycletoglutamatetransmissiontunesaneuralbrakeonseizureonset AT jihyungkim metabolicfluxfromthekrebscycletoglutamatetransmissiontunesaneuralbrakeonseizureonset AT chunghunlim metabolicfluxfromthekrebscycletoglutamatetransmissiontunesaneuralbrakeonseizureonset
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Metabolic flux from the Krebs cycle to glutamate transmission tunes a neural brake on seizure onset.

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