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

Jiwon Jeong,Chunghun Lim,Jongbin Lee,Ji-hyung Kim,Gaiti Hasan

doi:10.1371/journal.pgen.1009871

Jiwon Jeong, Chunghun Lim + Show 3 more

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https://doi.org/10.1371/journal.pgen.1009871

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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.

Highlights

Kohlschutter-Tonz syndrome (KTS) is a genetic disorder that manifests as developmental abnormalities such as tooth dysplasia, intellectual disability, and early-onset epileptic encephalopathy [1]
Kohlschutter-Tonz syndrome (KTS) is a neurodevelopmental disorder linked to two distinct genomic loci encoding the citrate transporter SLC13A5 and synaptic protein ROGDI, respectively
We discover that the metabolic flux of the Krebs cycle to glutamate biosynthesis plays a critical role in scaling seizure-relevant glutamate transmission

Summary

Introduction

Kohlschutter-Tonz syndrome (KTS) is a genetic disorder that manifests as developmental abnormalities such as tooth dysplasia, intellectual disability, and early-onset epileptic encephalopathy [1]. Animal models for ROGDI or SLC13A5 serve as essential genetic resources to elucidate the physiological function of the gene products and their mechanisms underlying the KTS pathogenesis. The Drosophila homolog of SLC13A5 is I’m not dead yet (Indy), named for the long lifespan of loss-of-function mutants [13], the longevity phenotype might be sensitive to genetic background or calorie intake [14,15,16]. As expected based on its citratetransporter activity, loss of Indy function phenocopies physiological changes in calorierestricted animals, including low body weight, low triglyceride levels, and high sensitivity to starvation [16,17]. Mitochondrial physiology is altered in Indy mutant flies (i.e., increased mitochondrial biogenesis, decreased electron transport chain function), likely via a mechanism dependent on peroxisome proliferator-activated receptor gamma coactivator-1α [16,17,18]

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