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

Minjong Kim, Donghoon Jang, Eunseok Yoo, Yangkyun Oh, Jun Young Sonn, Jongbin Lee, Yoonhee Ki, Hyo Jin Son, Onyou Hwang, Changwook Lee, Chunghun Lim, Joonho Choe

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11 Scopus citations

Abstract

Kohlschutter-Tönz 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.

Original languageEnglish
Article number11368
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - 1 Dec 2017

Bibliographical note

Funding Information:
We thank J. Dubnau, Bloomington Drosophila Stock Center, and the National Institute of Genetics for Drosophila strains. This work was supported by a grant from the Korea Health Technology R&D Project through the KHIDI funded by the Ministry of Health & Welfare, the Republic of Korea (HI16C1747) (C.Lim); a grant from the National Research Foundation (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP), the Republic of Korea (NRF-2016R1E1A2914795) (C.Lim); a grant from the NRF funded by the MSIP, the Republic of Korea (NRF-2016R1A2B4011111) (J.C.).

Publisher Copyright:
© 2017 The Author(s).

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