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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Citric Acid / metabolism
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Citric Acid Cycle / genetics
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Citric Acid Cycle / physiology*
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Dicarboxylic Acid Transporters / genetics
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Dicarboxylic Acid Transporters / metabolism
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Drosophila / genetics
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Drosophila / metabolism
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Glutamic Acid / genetics
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Glutamic Acid / metabolism*
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Male
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Metabolic Networks and Pathways / genetics
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Metabolic Networks and Pathways / physiology
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Mutation / genetics
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Neurons / metabolism
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Seizures / genetics
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Seizures / metabolism*
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Symporters / genetics
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Symporters / metabolism
Substances
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Dicarboxylic Acid Transporters
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Drosophila Proteins
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Indy protein, Drosophila
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Symporters
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Citric Acid
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Glutamic Acid
Grants and funding
This work was supported by grants from the Suh Kyungbae Foundation (SUHF-17020101[CL]); from the National Research Foundation funded by the Ministry of Science and Information & Communication Technology (MSIT), Republic of Korea (NRF-2018R1A5A1024261[CL]; NRF-2021M3A9G8022960[CL]), and by the Ministry of Education, Republic of Korea (NRF-2019R1I1A1A01063087[JL]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.