Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila

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Kohlschutter-Tonz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, we propose that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2017-09
Language
English
Article Type
Article
Keywords

KOHLSCHUTTER-TONZ SYNDROME; EPILEPTIC ENCEPHALOPATHY; PYRUVATE-CARBOXYLASE; REGULATES SLEEP; NEURONS; MUTANTS; SEIZURE; DEPRIVATION; MUTATIONS; GABA

Citation

SCIENTIFIC REPORTS, v.6, pp.32113

ISSN
2045-2322
DOI
10.1038/s41598-017-11941-3
URI
http://hdl.handle.net/10203/226286
Appears in Collection
BS-Journal Papers(저널논문)
Files in This Item
2016-Kim-Lim(SciRep).pdf(2.13 MB)Download
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