Fbxl4 Serves as a Clock Output Molecule that Regulates Sleep through Promotion of Rhythmic Degradation of the GABAA Receptor

Li, Qian; Li, Yi; Xiao, Wang; Qi, Junxia; Jin, Xi; Tong, Huawei; Zhou, Zikai; Zhang, Zi Chao; Han, Junhai

doi:10.1016/j.cub.2017.10.052

Cited by 37 publications

(39 citation statements)

References 44 publications

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“…RDL also cycles in l‐LNvs and is regulated by rhythmic degradation though the E3 ligase Fbxl4, whose transcription is clock controlled. As expected, Fbxl4 mutants have the opposite phenotype of wake mutants, with a shorter latency to sleep onset at dusk (Li et al., ).…”

Section: Clock Output Genessupporting

confidence: 64%

Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain

King

Sehgal

2018

Eur J of Neuroscience

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A central question in the circadian biology field concerns the mechanisms that translate ~24-hr oscillations of the molecular clock into overt rhythms. Drosophila melanogaster is a powerful system that provided the first understanding of how molecular clocks are generated and is now illuminating the neural basis of circadian behavior. The identity of ~150 clock neurons in the Drosophila brain and their roles in shaping circadian rhythms of locomotor activity have been described before. This review summarizes mechanisms that transmit time-of-day signals from the clock, within the clock network as well as downstream of it. We also discuss the identification of functional multisynaptic circuits between clock neurons and output neurons that regulate locomotor activity.

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Section: Clock Output Genessupporting

confidence: 64%

Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain

King

Sehgal

2018

Eur J of Neuroscience

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“…Comparably to the PDF‐ir large ventrolateral neurons (lLNvs) in the fruit fly (review: Helfrich‐Förster, ), a subpopulation of the PDF‐ir neurons in the Madeira cockroach that arborises in the lamina and the AME were suggested to control sleep wake cycles. Both, in fruit flies and the cockroach these PDF‐ir neurons are GABA‐sensitive (Gestrich et al., ; Li et al., ). In Drosophila the GABA A receptors in the sleep regulating PDF‐ir lLN v s are under circadian control (Li et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…Both, in fruit flies and the cockroach these PDF‐ir neurons are GABA‐sensitive (Gestrich et al., ; Li et al., ). In Drosophila the GABA A receptors in the sleep regulating PDF‐ir lLN v s are under circadian control (Li et al., ). It is possible that this is also true for the respective PDF‐ir neurons in the cockroach, as preliminary experiments found endogenous rhythms of GABA sensitivity of AME neurons in vitro (Maria Giese and Monika Stengl, unpublished).…”

Section: Discussionmentioning

confidence: 99%

Circadian pacemaker neurons of the Madeira cockroach are inhibited and activated by GABA_A and GABA_B receptors

Giese

Wei

Stengl

2018

Eur J of Neuroscience

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GABA is the most abundant neurotransmitter in the circadian pacemaker circuits of mammals and insects. In the Madeira cockroach the accessory medulla (AME) in the brain′s optic lobes is the circadian clock that orchestrates rest‐activity rhythms in synchrony with light dark cycles. Three prominent GABAergic tracts connect the AME to termination sites of compound eye photoreceptors in the lamina and medulla. Parallel GABAergic light entrainment pathways were suggested to either advance or delay the clock for adjustment to changing photoperiods. In agreement with this hypothesis GABA activated or inhibited AME clock neurons, allowing for the distinction of three different GABA response types. Here, we examined which GABA receptors are responsible for these response types. We found that both ionotropic GABAA receptors and metabotropic GABAB receptors were expressed in AME clock cells. Via different signalling pathways, either one of them could account for all three GABA response types. The muscimol‐dependently activated GABAA receptor formed a chloride channel, while the SKF 97541‐dependently activated GABAB receptor signalled via G‐proteins, apparently targeting potassium channels. Expression of chloride exporters or importers determined whether GABAA receptor activation hyper‐ or depolarized AME neurons. For GABAB receptor responses second messenger gated channels present in the clock cells appeared to decide about the polarity of the GABA response. In summary, circadian clock neurons co‐expressed inhibitory and/or excitatory GABAA and GABAB receptors in various combinations, while cotransporter expression and the set of second messenger gated ion channels present allowed for distinct signalling in different clock neurons.

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“…Although the biological basis of classification of initiating and maintaining sleep is unknown, sleep initiation is suggested to be uncoupled from sleep maintenance in Drosophila. In particular, hyperactivity of l-LNvs resulted in increased sleep latency and GABA A receptor played a critical role in the regulation Chung et al, 2009;Li et al, 2017). Another study shows that sleep initiation is dependent on the amnesiac gene expression (Liu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Control of Sleep Onset by Shal/K_v4 Channels inDrosophilaCircadian Neurons

Gao

Zhang

et al. 2018

J. Neurosci.

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Sleep is highly conserved across animal species. Both wake- and sleep-promoting neurons are implicated in the regulation of wake-sleep transition at dusk in However, little is known about how they cooperate and whether they act via different mechanisms. Here, we demonstrated that in female, sleep onset was specifically delayed by blocking the Shaker cognate L channels [Shal; also known as voltage-gated K channel 4 (K4)] in wake-promoting cells, including large ventral lateral neurons (l-LNvs) and pars intercerebralis (PI), but not in sleep-promoting dorsal neurons (DN1s). Delayed sleep onset was also observed in males by blocking K4 activity in wake-promoting neurons. Electrophysiological recordings show that K4 channels contribute A-type currents in LNvs and PI cells, but are much less conspicuous in DN1s. Interestingly, blocking K4 in wake-promoting neurons preferentially increased firing rates at dusk ∼ZT13, when the resting membrane potentials and firing rates were at lower levels. Furthermore, pigment-dispersing factor (PDF) is essential for the regulation of sleep onset by K4 in l-LNvs, and downregulation of PDF receptor (PDFR) in PI neurons advanced sleep onset, indicating K4 controls sleep onset via regulating PDF/PDFR signaling in wake-promoting neurons. We propose that K4 acts as a sleep onset controller by suppressing membrane excitability in a clock-dependent manner to balance the wake-sleep transition at dusk. Our results have important implications for the understanding and treatment of sleep disorders such as insomnia. The mechanisms by which our brains reversibly switch from waking to sleep state remain an unanswered and intriguing question in biological research. In this study, we identified that Shal/K4, a well known voltage-gated K channel, acts as a controller of wake-sleep transition at dusk in circadian neurons. We find that interference of K4 function with a dominant-negative form (DNK4) in subsets of circadian neurons specifically disrupts sleep onset at dusk, although K4 itself does not exhibit circadian oscillation. K4 preferentially downregulates neuronal firings at ZT9-ZT17, supporting that it plays an essential role in wake-sleep transition at dusk. Our findings may help understand and eventually treat sleep disorders such as insomnia.

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Fbxl4 Serves as a Clock Output Molecule that Regulates Sleep through Promotion of Rhythmic Degradation of the GABAA Receptor

Cited by 37 publications

References 44 publications

Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain

Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain

Circadian pacemaker neurons of the Madeira cockroach are inhibited and activated by GABA_A and GABA_B receptors

Control of Sleep Onset by Shal/K_v4 Channels inDrosophilaCircadian Neurons

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Fbxl4 Serves as a Clock Output Molecule that Regulates Sleep through Promotion of Rhythmic Degradation of the GABAA Receptor

Cited by 37 publications

References 44 publications

Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain

Molecular and circuit mechanisms mediating circadian clock output in the Drosophila brain

Circadian pacemaker neurons of the Madeira cockroach are inhibited and activated by GABAA and GABAB receptors

Control of Sleep Onset by Shal/Kv4 Channels inDrosophilaCircadian Neurons

Contact Info

Product

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Circadian pacemaker neurons of the Madeira cockroach are inhibited and activated by GABA_A and GABA_B receptors

Control of Sleep Onset by Shal/K_v4 Channels inDrosophilaCircadian Neurons