Kohlschutter-Tönz syndrome (KTS) is a rare genetic disorder characterized by severe developmental delay with neurological dysfunction such as epilepsy, psychomotor regression and intellectual disability. While genetic mutations in a human homolog of Rogdi gene have been linked to the development of KTS, its neural basis remains elusive. Here we establish a Drosophila model of KTS to demonstrate a novel role of Rogdi in GABAergic transmission. Our genetic screen initially identified a hypomorphic mutation in Drosophila Rogdi that supressed daily baseline sleep. The short sleep phenotypes were rescued by transgenic Rogdi expression in GABAergic neurons or by the oral administration of a GABA transaminase inhibitor that enhances GABAergic signaling. An enhancer trap line originated from Rogdi locus displayed its expression in sleep-regulatory neurons of adult fly brains, including GABA-positive neurons. Furthermore, RNA interference-mediated depletion of vesicular GABA transporter in Rogdi-expressing neurons decreased sleep, largely phenocoping Rogdi mutants. Notably, Rogdi effects on sleep were masked by genetic or pharmacological inhibition of dopaminergic transmission, newly defining a dopaminergic circuit as a downstream target of Rogdi-dependent sleep. Taken together, these data suggest that ROGDI sustains GABAergic transmission to promote sleep. Given the strong relevance of KTS phenotypes to GABA, our findings provide the first neural clues important for understanding KTS pathogenesis
