Sleep and Synaptic Homeostasis: Structural Evidence in
            <i>Drosophila</i>

Bushey, Daniel; Tononi, Giulio; Cirelli, Chiara

doi:10.1126/science.1202839

Cited by 316 publications

(287 citation statements)

References 37 publications

(44 reference statements)

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“…37 In addition, dysregulation of mTOR signaling is found in mouse and Drosophila models of FXS, which show that loss of FMRP leads to altered circadian rhythm behaviors and sleep-dependent synaptic renormalization. 38 Also, in human studies, FXS patients show altered mTOR signaling. 39 Moreover, these findings suggest that MBD5, RAI1, and FMR1 dysregulation could disrupt the mTOR signaling pathway, disrupting mammalian period (PER (1-2)) genes, which have key roles in photic entrainment of the circadian clock to light pulses.…”

Section: Discussionmentioning

confidence: 99%

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

et al. 2014

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Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/ snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders. Significant sleep problems are highly prevalent in individuals with ASD. 2 Parents of children with ASD report 50-80% prevalence of sleep problems compared with a 9-50% prevalence rate reported by parents of age-matched typically developing children. 2 Common sleep etiological factors that are present in children with ASD are rapid eye movement sleep abnormalities, dysregulation of melatonin synthesis, difficulty in settling to sleep, night waking, irregular sleep patterns, short-duration sleep, and daytime sleepiness. 2,3 Persistent sleep problems are thought to adversely affect cognitive, physical, and social function, learning, mood, and behavior in these individuals and, in addition, cause significant stress for families and caretakers. 3 Better understanding of the sleep difficulties experienced by children with ASD may reduce the adverse effects and decrease family stress, possibly with targeted therapies.

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Section: Discussionmentioning

confidence: 99%

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

et al. 2014

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“…Insects are known to go through rest phases that resemble key features of sleep [Drosophila (Hendricks et al, 2000;Shaw et al, 2000); honeybee (Kaiser, 1988)]. In Drosophila, the genes and signaling cascades that control sleep are already well understood (Sehgal and Mignot, 2011), and some of these regulatory systems can be related to synaptic plasticity and memory consolidation (Foltenyi et al, 2007;Bushey et al, 2011;Seugnet et al, 2011;Wu and Raizen, 2011). The neural networks involved in these cellular processes highlight the role of the mushroom body (Joiner et al, 2006;Guo et al, 2011) and an identified protocerebral cell group, the octopamine-containing neurons in the pars intercerebralis (Crocker et al, 2010), possibly also involved in synaptic plasticity and memory consolidation.…”

Section: Discussionmentioning

confidence: 99%

Honeybees consolidate navigation memory during sleep

Beyaert

Greggers

Menzel

2012

Journal of Experimental Biology

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SUMMARYSleep is known to support memory consolidation in animals, including humans. Here we ask whether consolidation of novel navigation memory in honeybees depends on sleep. Foragers were exposed to a forced navigation task in which they learned to home more efficiently from an unexpected release site by acquiring navigational memory during the successful homing flight. This task was quantified using harmonic radar tracking and applied to bees that were equipped with a radio frequency identification device (RFID). The RFID was used to record their outbound and inbound flights and continuously monitor their behavior inside the colony, including their rest during the day and sleep at night. Bees marked with the RFID behaved normally inside and outside the hive. Bees slept longer during the night following forced navigation tasks, but foraging flights of different lengths did not lead to different rest times during the day or total sleep time during the night. Sleep deprivation before the forced navigation task did not alter learning and memory acquired during the task. However, sleep deprivation during the night after forced navigation learning reduced the probability of returning successfully to the hive from the same release site. It is concluded that consolidation of novel navigation memory is facilitated by night sleep in bees.

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“…84,85 Another conjecture is that sleep acts to downscale the strengths of synaptic connections, so that increases in synaptic strength during wakefulness stay below mechanistically infeasible limits. 8,26,[86][87][88][89] This hypothesis is related to the earlier demonstration that the firing by neurons and the strengths of their synapses are homeostatically increased or decreased to maintain firing rates within certain boundaries. 90 The synaptic downscaling hypothesis posits, in effect, that the previously characterized recalibration of synaptic strengths 90 does not suffice during wakefulness, and that sleep is required for a further downscaling.…”

Section: Introductionmentioning

confidence: 91%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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Sleep and Synaptic Homeostasis: Structural Evidence in Drosophila

Cited by 316 publications

References 37 publications

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

Honeybees consolidate navigation memory during sleep

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

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