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 (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.Author summary: Kohlschütter-Tönz syndrome (KTS) is a neurodevelopmental disorder linked to two distinct genomic loci encoding the citrate transporter SLC13A5 and synaptic protein ROGDI, respectively. An early-onset seizure is the most prominent neurological symptom in KTS patients, yet how these genes contribute to the control of seizure susceptibility remains poorly understood. Our study establishes behavioral models of seizure in Drosophila mutants of KTS-associated genes and demonstrates a genetic, metabolic, and neural pathway of seizure suppression. We discover that the metabolic flux of the Krebs cycle to glutamate biosynthesis plays a critical role in scaling seizure-relevant glutamate transmission. We further map this seizure-suppressing pathway to a surprisingly small number of glutamatergic neurons and their ionotropic glutamate transmission onto a key sleep-promoting locus in the adult fly brain. Given that the excitatory amino acid glutamate is considered a general seizure-promoting neurotransmitter, our findings illustrate how glutamatergic transmission can have opposing effects on seizure susceptibility in the context of a micro-neural circuit, possibly explaining drug-resistant epilepsy. This seizure-suppressing locus in the Drosophila brain is also implicated in metabolism, circadian rhythms, and sleep, revealing the conserved neural principles of their intimate interaction with epilepsy across species.