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.
Highlights
Given that Rogdi homologs are relatively well conserved in higher eukaryotes, animal models may facilitate our understanding of Rogdi-dependent neural processes
To further validate our original hypothesis above, we examined if gamma-aminobutyric acid (GABA) receptor agonists could suppress short diaminobutyric acid (GAT inhibitor); EOS, ethanolamine O-sulfate (GABA-T inhibitor); GABAA-R, ionotropic GABA receptor; GABAB-R, metabotropic GABA receptor; GABA-T, GABA transaminase; GAD1, glutamate decarboxylase 1; GAT, GABA transporter; SKF-97541, 3-Aminopropyl(methyl)phosphinic acid (GABAB-R agonist); THIP, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (GABAA-R agonist); VGAT, vesicular GABA transporter. (b,c) Oral administration of EOS (b) or DABA (c) rescues sleep quantity and sleep latency in
We established the first genetic model of the Kohlschutter-Tönz syndrome (KTS)-associated disease gene Rogdi to demonstrate that Rogdi functions as a novel sleep-promoting factor in GABAergic neurons by promoting GABA transmission
Summary
Given that Rogdi homologs are relatively well conserved in higher eukaryotes, animal models may facilitate our understanding of Rogdi-dependent neural processes. Sequence analyses of Rogdi homologs revealed a putative leucine zipper (ZIP) motif, which could mediate the dimerization of DNA-binding basic ZIP (bZIP) transcription factors[5]. Few or no studies have demonstrated the biological activity of Rogdi[9] and genetic models for Rogdi homologs have not been reported yet. In the course of our genetic studies to elucidate genes and regulatory pathways involved in sleep behaviors, we identified novel sleep mutant alleles in the Drosophila Rogdi gene. We employed the sleep-promoting effects of Rogdi as a readout of its neural function and demonstrated that Rogdi acts cell-autonomously in GABAergic neurons to enhance metabotropic GABA transmission and thereby sustain sleep. Dopaminergic rescue of Rogdi mutant sleep revealed a novel sleep-regulatory mechanism that functionally links a specific subset of sleep-promoting GABAergic neurons to a wake-promoting dopaminergic pathway. A well penetrated phenotype in KTS patients, implicates GABAergic transmission[10,11,12] and sleep disorders[13,14,15,16], our findings provide an important genetic clue to understanding the molecular and neural pathogenesis of KTS
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