AANAT1 functions in astrocytes to regulate sleep homeostasis

Davla, Sejal; Artiushin, Gregory; Li, Yongjun; Chitsaz, Daryan; Li, Sally; Sehgal, Amita; Meyel, Donald J. van

doi:10.7554/elife.53994

Cited by 30 publications

(24 citation statements)

References 60 publications

(77 reference statements)

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“…Thus, we tested whether rumpel Δ +cherry null mutants show an abnormal sleep behavior. We noted a significant increase in day sleep compared to w 1118 flies, similar to what was observed for taurin transporter (EAAT2) ( Davla et al, 2020 ; Stahl et al, 2018 ) ( Fig. 4 F,G).…”

Section: Resultssupporting

confidence: 82%

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Redundant functions of the SLC5A transporters Rumpel, Bumpel, and Kumpel in ensheathing glial cells

et al. 2022

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Neuronal processing is energy demanding, and relies on sugar metabolism. To nurture the Drosophila nervous system, the blood-brain barrier forming glial cells take up trehalose from the hemolymph and then distribute the metabolic products further to all neurons. This function is provided by glucose and lactate transporters of the solute carrier (SLC) 5A family. Here we identified three SLC5A genes that are specifically expressed in overlapping sets of CNS glial cells, rumpel, bumpel and kumpel. We generated mutants in all genes and all mutants are viable and fertile, lacking discernible phenotypes. Loss of rumpel causes subtle locomotor phenotypes and flies display increased daytime sleep. In addition, in bumpel kumpel double mutants, and to an even greater extent in rumpel bumpel kumpel triple mutants, oogenesis is disrupted at the onset of the vitollegenic phase. This indicates a partially redundant functions between these genes. Rescue experiments exploring this effect indicate that oogenesis can be affected by CNS glial cells. Moreover, expression of heterologous mammalian SLC5A transporters, with known transport properties, suggest that Bumpel and/or Kumpel transport glucose or lactate. Overall, our results imply a redundancy in SLC5A nutrient sensing functions in Drosophila glial cells, affecting ovarian development and behavior.

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Section: Resultssupporting

confidence: 82%

“…Ensheathing glial cells have been associated with sleep phenotypes ( Davla et al, 2020 ; Stahl et al, 2018 ). Thus, we tested whether rumpel Δ +cherry null mutants show an abnormal sleep behavior.…”

Section: Resultsmentioning

confidence: 99%

Redundant functions of the SLC5A transporters Rumpel, Bumpel, and Kumpel in ensheathing glial cells

et al. 2022

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“…Astrocyte-like glia have a distinctive shape that allows remarkably close physical contact with synapses and is thought to be important for the clearance of neurotransmitters in the synaptic space (Freeman, 2015). In support of this, arylalkylamine N-acetyltransferase 1 (AANAT1), which acetylates and inactivates monoamines, acts in astrocytes to affect sleep (Davla et al, 2020). Also, calcium signaling in astrocytes appears to contribute to sleep need (Blum et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Parents flies are cleared after seven days, and F1 progenies are collected after twelve days. On day17, 5-7 days old female flies are loaded into locomotor tubes for behavior tests as previously described (Davla et al, 2020). Locomotor tubes are 60 mm glass tubes vaxed with 2% agar with 5% sucrose as fly food on one side, and the yarn is put on the other side to restrain the behavior of flies inside the glass tubes.…”

Section: Star⋆methodsmentioning

confidence: 99%

Ecdysone acts through cortex glia to regulate sleep in Drosophila

Haynes

Zhang

et al. 2022

Preprint

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Steroid hormones are attractive candidates for transmitting long-range signals to affect behavior. These lipid-soluble molecules derived from dietary cholesterol easily penetrate the brain and act through nuclear hormone receptors (NHRs) that function as transcription factors. To determine the extent to which NHRs affect sleep: wake cycles, we knocked down each of the 18 highly conserved NHRs found in Drosophila adults and report that the ecdysone receptor (EcR) and its direct downstream NHR Eip75B (E75) act in glia to regulate the rhythm and amount of sleep. Halloween genes, a set of ecdysone synthesis genes, have little to no expression in the fly brain, while mRNA levels of the ecdysone target E75 cycle in the fly head, suggesting that glial ecdysone comes from the periphery and may enter the brain more at night. Anti-EcR staining localizes to the cortex glia in the brain and functional screening of glial subtypes revealed that EcR functions in adult cortex glia to affect sleep. Cortex glia are implicated in lipid metabolism, which appears to be relevant for actions of ecdysone as ecdysone treatment reduces lipid droplet size in these cells. In addition, sleep-promoting effects of exogenous ecdysone are diminished in Lsd-2 mutant flies, which are lean and deficient in lipid accumulation. We propose that ecdysone is a systemic secreted factor that modulates sleep by stimulating lipid metabolism in cortex glia.

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“…AANAT1, an astrocyte gene that acetylates and inactivates monoamine, is found critical for the regulation of serotonin and dopamine levels in the brain. Studies have shown that AANAT1 can acetylate dopamine and affect melatonin production to regulate sleep ( Cheng et al, 2012 ; Kulczykowska et al, 2017 ; Fagan et al, 2021 ), and it can limit the accumulation of serotonin and dopamine in the brain after sleep deprivation ( Nall and Sehgal, 2014 ; Davla et al, 2020 ). Sleep deprivation leads to a significant increase in serotonin and dopamine, and this effect is reversed by astrocyte, but not neuron-specific AANAT1 mutation flies ( Davla et al, 2020 ), suggesting that astrocyte-mediated monoamine metabolism is important for sleep homeostasis.…”

Section: Astrocytic and Microglial Roles In Sleep Or Sleep Disturbancementioning

confidence: 99%

Possible Neuropathology of Sleep Disturbance Linking to Alzheimer’s Disease: Astrocytic and Microglial Roles

Xiao

Liu

Wang

et al. 2022

Front. Cell. Neurosci.

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Sleep disturbances not only deteriorate Alzheimer’s disease (AD) progress by affecting cognitive states but also accelerate the neuropathological changes of AD. Astrocytes and microglia are the principal players in the regulation of both sleep and AD. We proposed that possible astrocyte-mediated and microglia-mediated neuropathological changes of sleep disturbances linked to AD, such as astrocytic adenosinergic A1, A2, and A3 regulation; astrocytic dopamine and serotonin; astrocyte-mediated proinflammatory status (TNFα); sleep disturbance-attenuated microglial CX3CR1 and P2Y12; microglial Iba-1 and astrocytic glial fibrillary acidic protein (GFAP); and microglia-mediated proinflammatory status (IL-1b, IL-6, IL-10, and TNFα). Furthermore, astrocytic and microglial amyloid beta (Aβ) and tau in AD were reviewed, such as astrocytic Aβ interaction in AD; astrocyte-mediated proinflammation in AD; astrocytic interaction with Aβ in the central nervous system (CNS); astrocytic apolipoprotein E (ApoE)-induced Aβ clearance in AD, as well as microglial Aβ clearance and aggregation in AD; proinflammation-induced microglial Aβ aggregation in AD; microglial-accumulated tau in AD; and microglial ApoE and TREM2 in AD. We reviewed astrocytic and microglial roles in AD and sleep, such as astrocyte/microglial-mediated proinflammation in AD and sleep; astrocytic ApoE in sleep and AD; and accumulated Aβ-triggered synaptic abnormalities in sleep disturbance. This review will provide a possible astrocytic and microglial mechanism of sleep disturbance linked to AD.

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AANAT1 functions in astrocytes to regulate sleep homeostasis

Cited by 30 publications

References 60 publications

Redundant functions of the SLC5A transporters Rumpel, Bumpel, and Kumpel in ensheathing glial cells

Redundant functions of the SLC5A transporters Rumpel, Bumpel, and Kumpel in ensheathing glial cells

Ecdysone acts through cortex glia to regulate sleep in Drosophila

Possible Neuropathology of Sleep Disturbance Linking to Alzheimer’s Disease: Astrocytic and Microglial Roles

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