The Taurine Transporter Eaat2 Functions in Ensheathing Glia to Modulate Sleep and Metabolic Rate

Stahl, Bethany A.; Peco, Emilie; Davla, Sejal; Murakami, Kazuma; Moreno, Nicolás A. Caicedo; Meyel, Donald J. van; Keene, Alex C.

doi:10.1016/j.cub.2018.10.039

Cited by 54 publications

(51 citation statements)

References 49 publications

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“…Astrocytes are particularly well-suited for regulating sleep in this way because they have ramified processes that infiltrate neuropil regions to lie in close proximity to synapses. 11 AANAT1 also functions in neurons to regulate baseline sleep, which highlights the idea that cellular context has profound impact on AANAT1 function in sleep regulation. In light of this, we note that loss of the related enzyme aanat2 in zebrafish larvae decreases baseline sleep [36], which could be attributed to a loss of melatonin since the AANAT1 product N-acetylserotonin is an intermediate in the synthesis of melatonin in vertebrates [31].…”

Section: I-l)mentioning

confidence: 92%

AANAT1 functions in astrocytes to regulate sleep homeostasis

Davla

Artiushin

Chitsaz

et al. 2019

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The monoamine catabolic enzyme arylalkylamine N-acetyltransferase 1 (AANAT1) is expressed by astrocytes and subsets of serotonergic, glutamatergic, GABAergic and cholinergic neurons in the adult brain of Drosophila.AANAT1 limits accumulation of serotonin and dopamine in the brain upon sleep deprivation.Loss of AANAT1 from astrocytes, but not from neurons, causes flies to increase their daytime rebound sleep in response to overnight sleep deprivation. 3 Summary Characteristic features of sleep are conserved among species [1], and from humans to insects sleep is influenced by neural circuits involving monoamines such as serotonin and dopamine [2]. Glial cells have been increasingly implicated in mechanisms of baseline and homeostatic sleep regulation in mammals and flies [3-11], but it remains unknown whether and how glia might influence monoaminergic control of sleep. Sleep is regulated by circadian rhythms and a homeostatic drive to compensate for prolonged wakefulness, andgrowing evidence suggests that neural mechanisms controlling homeostatic sleep can be discriminated from those controlling baseline sleep [12][13][14][15]. In Drosophila, mutants of arylalkylamine N-acetyltransferase 1 (AANAT1 lo ) have normal baseline amounts of sleep and motor activity, but increased rebound sleep following deprivation [16]. AANAT1 can acetylate and inactivate monoamines in vitro [17], but the role of AANAT1 in vivo remains poorly understood. We find AANAT1 to be expressed in astrocytes and subsets of neurons in the adult Drosophila brain, with levels in astrocytes declining markedly overnight. In sleep-deprived AANAT1 mutant flies, heightened rebound sleep is accompanied by increased serotonin and dopamine levels in the brain. In neurons, AANAT1 functions to limit the quantity and consolidation of nighttime sleep, but in astrocytes AANAT1 constrains the amount of rebound sleep that flies take in response to sleep deprivation.These findings distinguish sleep-control functions of AANAT1 in neurons and astrocytes, and identify a critical role for astrocytes in the regulation of monoamine bioavailability and calibration of the response to sleep need. 4 Results and DiscussionWe generated antiserum to AANAT1 (known previously as Dopamine acetyltransferase (Dat) and confirmed its specificity with immunohistochemistry (IHC) in the embryonic CNS. AANAT1 immunoreactivity was observed in the cytoplasm of many cells (Fig. 1A) but was absent in age-matched embryos that were homozygous for a deletion of the entire AANAT1 gene (Fig. 1B). In adult brains, AANAT1 was co-labeled with Bruchpilot (nc82, Fig. 1C), a presynaptic marker that labels neuropil regions. We found that AANAT1 was expressed in neurons (Elav + , Fig. 1D,D') and glia (Repo + , Fig.

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Section: I-l)mentioning

confidence: 92%

AANAT1 functions in astrocytes to regulate sleep homeostasis

Davla

Artiushin

Chitsaz

et al. 2019

Preprint

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“…Metabolic rate was measured using the Sleep and Activity Metabolic Monitor (SAMM) system at 367 25 ºC through indirect calorimetry using a stop-flow, push-through respirometry system (Sable 368 Systems International). Metabolic rate in group-housed adult flies was measured as previously 369 described (Stahl et al, 2018;Stahl et al, 2017). Briefly, the experimental system assessed 370 baseline CO2 levels from an empty chamber to measure CO2 production and O2 consumption 371 from 25 male adult flies.…”

Section: Indirect Calorimetry 366mentioning

confidence: 99%

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Botero

Stahl

Grenci

et al. 2019

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1Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing patients to a range of 2 features, the most characteristic of which include areas of abnormal skin pigmentation and 3 benign tumors associated with peripheral nerves, termed neurofibromas. Less common, but 4 more serious symptoms also include malignant peripheral nerve sheath tumors, other 5 malignancies, and learning disabilities. The NF1 gene encodes neurofibromin, a large protein 6 that functions as a negative regulator of Ras signaling and mediates pleiotropic cellular and 7 organismal function. Recent evidence suggests NF1 may regulate metabolism, though the 8 mechanisms are unknown. Here we show that the Drosophila ortholog of NF1, dNf1 regulates 9 metabolic homeostasis in fruit flies by functioning within a discrete brain circuit. Loss of dNf1 10 increases metabolic rate and feeding, enhances starvation susceptibility, and decreases lipid 11 stores while increasing lipid turnover rate. The increase in metabolic rate is independent of 12 locomotor activity (grooming), and maps to a subset of neurons in the ventral nervous system. 13The feeding and metabolic rate effects are due to loss of dNf1 in the same set of neurons, 14suggesting that increased feeding may be a compensatory effect driven by the increase in 15 metabolic rate and lipid turnover. Finally, we show that the Ras GAP-related domain of 16 neurofibromin is required for normal metabolism, demonstrating that Ras signaling downstream 17 of dNf1 mediates the metabolic effects. These data demonstrate that dNf1 regulates metabolic 18 rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may 19 represent a pathophysiological mechanism in NF1, and provide a platform for investigating the 20 cellular role of neurofibromin in metabolic homeostasis. 21

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“…Glial regulation of synaptic function and neuronal homeostasis is critical for proper sleep [1–3]. The Drosophila brain contains five distinct types of glia: perineural and subperineural glia, which form the blood-brain barrier; cortex glia; astrocyte-like glia, which regulate synaptic function; and ensheathing glia, which surround neuropil [4–6].…”

Section: Resultsmentioning

confidence: 99%

“…The Drosophila brain contains five distinct types of glia: perineural and subperineural glia, which form the blood-brain barrier; cortex glia; astrocyte-like glia, which regulate synaptic function; and ensheathing glia, which surround neuropil [4–6]. Multiple glial subtypes have been identified that regulate sleep in Drosophila [1–3]. Moreover, glial dysfunction is associated with aging, and numerous models of neurodegeneration in flies [7–11].…”

Section: Resultsmentioning

confidence: 99%

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Sleep regulates the glial engulfment receptor Draper to promote Wallerian degeneration

Stahl

Jaggard

Keene

2019

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Highlights 1 2 • Sleep deprivation impairs Wallerian degeneration in fruit flies.• Pharmacological induction of sleep accelerates Wallerian degeneration.• Sleep promotes innervation surrounding damaged neurites by phagocytic glia.• Sleep increases levels of the glial activation markers Draper and Stat92E. 3 Summary 4 Sleep, a universal behavior, is critical for diverse aspects of brain function. Chronic sleep 5 disturbance is associated with numerous health consequences, including neurodegenerative 6 disease and cognitive decline. Neurite damage due to apoptosis, trauma, or genetic factors is a 7 common feature of aging, and clearance of damaged neurons is essential for maintenance of 8 brain function. In the central nervous system, damaged neurites are cleared by Wallerian 9 degeneration, in which activated microglia and macrophages engulf damaged neurons. The fruit 10 fly Drosophila melanogaster provides a powerful model for investigating the relationship 11 between sleep and Wallerian degeneration. Several lines of evidence suggest that glia influence 12 sleep duration, sleep-mediated neuronal homeostasis, and clearance of toxic substances during 13 sleep, raising the possibility that glial engulfment of damaged axons is regulated by sleep. To 14 explore this possibility, we axotomized olfactory receptor neurons and measured the effects of 15 sleep loss or gain on the clearance of damaged neurites. Mechanical sleep deprivation impaired 16 the clearance of damaged neurites, whereas the sleep-promoting drug gaboxadol accelerated 17 clearance. In sleep-deprived animals, multiple markers of glial activation were delayed, 18 including activation of the JAK/STAT pathway, upregulation of the cell corpse engulfment 19 receptor Draper, and innervation of the antennal lobe by glial membranes. These markers were 20 all enhanced when sleep was induced in gaboxadol-treated flies. Taken together, these findings 21 reveal a critical role for sleep in regulation glial activation and engulfment following axotomy, 22 providing a platform for further investigations of the molecular mechanisms underlying sleep-23 dependent modulation of glial function and neurite clearance. Results and Discussion 1 Glial regulation of synaptic function and neuronal homeostasis is critical for proper sleep [1-3]. 2The Drosophila brain contains five distinct types of glia: perineural and subperineural glia, which 3 form the blood-brain barrier; cortex glia; astrocyte-like glia, which regulate synaptic function; and 4 ensheathing glia, which surround neuropil [4][5][6]. Multiple glial subtypes have been identified that 5 regulate sleep in Drosophila [1-3]. Moreover, glial dysfunction is associated with aging, and 6 numerous models of neurodegeneration in flies [7-11]. Despite these bidirectional interactions 7 between glia and sleep, surprisingly little is known about the mechanisms through which sleep-8 deprivation impacts glial function, and how this contributes to neurodegenerative disease. 9 10 Experimental ablation of the antennae results in ax...

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The Taurine Transporter Eaat2 Functions in Ensheathing Glia to Modulate Sleep and Metabolic Rate

Cited by 54 publications

References 49 publications

AANAT1 functions in astrocytes to regulate sleep homeostasis

AANAT1 functions in astrocytes to regulate sleep homeostasis

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Sleep regulates the glial engulfment receptor Draper to promote Wallerian degeneration

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