The voltage-gated potassium channel Shaker promotes sleep via thermosensitive GABA transmission.

Genes and neural circuits coordinately regulate animal sleep. However, it remains elusive how these endogenous factors shape sleep upon environmental changes. Here, we demonstrate that Shaker (Sh)-expressing GABAergic neurons projecting onto dorsal fan-shaped body (dFSB) regulate temperature-adaptive sleep behaviors in Drosophila. Loss of Sh function suppressed sleep at low temperature whereas light and high temperature cooperatively gated Sh effects on sleep. Sh depletion in GABAergic neurons partially phenocopied Sh mutants. Furthermore, the ionotropic GABA receptor, Resistant to dieldrin (Rdl), in dFSB neurons acted downstream of Sh and antagonized its sleep-promoting effects. In fact, Rdl inhibited the intracellular cAMP signaling of constitutively active dopaminergic synapses onto dFSB at low temperature. High temperature silenced GABAergic synapses onto dFSB, thereby potentiating the wake-promoting dopamine transmission. We propose that temperature-dependent switching between these two synaptic transmission modalities may adaptively tune the neural property of dFSB neurons to temperature shifts and reorganize sleep architecture for animal fitness.

Sleep-promoting effects of threonine link amino acid metabolism in Drosophila neuron to GABAergic control of sleep drive.

Emerging evidence indicates the role of amino acid metabolism in sleep regulation. Here we demonstrate sleep-promoting effects of dietary threonine (SPET) in Drosophila. Dietary threonine markedly increased daily sleep amount and decreased the latency to sleep onset in a dose-dependent manner. High levels of synaptic GABA or pharmacological activation of metabotropic GABA receptors (GABAB-R) suppressed SPET. By contrast, synaptic blockade of GABAergic neurons or transgenic depletion of GABAB-R in the ellipsoid body R2 neurons enhanced sleep drive non-additively with SPET. Dietary threonine reduced GABA levels, weakened metabotropic GABA responses in R2 neurons, and ameliorated memory deficits in plasticity mutants. Moreover, genetic elevation of neuronal threonine levels was sufficient for facilitating sleep onset. Taken together, these data define threonine as a physiologically relevant, sleep-promoting molecule that may intimately link neuronal metabolism of amino acids to GABAergic control of sleep drive via the neuronal substrate of sleep homeostasis. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

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

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.

Warming Up Your Tick-Tock: Temperature-Dependent Regulation of Circadian Clocks.

Circadian clocks are endogenous time-keeping mechanisms to adaptively coordinate animal behaviors and physiology with daily environmental changes. So far many circadian studies in model organisms have identified evolutionarily conserved molecular frames of circadian clock genes in the context of transcription-translation feedback loops. The molecular clockwork drives cell-autonomously cycling gene expression with ~24-hour periodicity, which is fundamental to circadian rhythms. Light and temperature are two of the most potent external time cues to reset the circadian phase of the internal clocks, yet relatively little is known about temperature-relevant clock regulation. In this review, we describe recent findings on temperature-dependent clock mechanisms in homeothermic mammals as compared with poikilothermic Drosophila at molecular, neural, and organismal levels. We propose thermodynamic transitions in RNA secondary structures might have been potent substrates for the molecular evolution of temperature-relevant post-transcriptional mechanisms. Future works should thus validate the potential involvement of specific post-transcriptional steps in temperature-dependent plasticity of circadian clocks.