Drosophila genetic models of Kohlschutter-Tönz syndrome uncover metabolic control of seizure susceptibility via glutamatergic transmission

Abstract

Kohlschutter-Tönz syndrome (KTS) is a rare genetic disease that manifests neurological dysfunctions such as seizure and intellectual disability. Rogdi and sodium-dependent citrate cotransporter SLC13A5 are two evolutionarily conserved genes that have been implicated in the development of KTS, yet their pathogenic mechanisms are not fully understood. Here we report that Rogdi and I’m not dead yet (Indy), a Drosophila SLC13A5 homolog, share a common neural pathway to suppress seizure via glutamatergic transmission. Loss of Rogdi or Indy function in motor neurons, including glutamatergic neurons, caused seizure-like behaviors in a bang-sensitive manner. Genetic enhancement of glutamate transmission was sufficient to suppress their seizure phenotypes whereas genetic or pharmacological silencing of NMDA receptors induced bang-sensitive seizure even in wild-type. Interestingly, glutamatergic depletion of metabolic enzymes involved in the citric acid cycle phenocopied Drosophila KTS models. On the other hand, oral administration of alpha-ketoglutarate, a rate-limiting substrate of the metabolic pathway, ameliorated the seizure phenotypes in Rogdi or Indy mutants. Our data positively link the flux of the metabolic citric acid cycle to the scale of glutamate transmission for the control of KTS-relevant seizure susceptibility. These findings also explain the resistance of the early-onset seizure observed in KTS patients to general anti-epileptic drugs.