Sleep and Synaptic Homeostasis: Structural Evidence in Drosophila

Department of Psychiatry, University of Wisconsin, Madison, WI 53719, USA.
Science (Impact Factor: 33.61). 06/2011; 332(6037):1576-81. DOI: 10.1126/science.1202839
Source: PubMed


The functions of sleep remain elusive, but a strong link exists between sleep need and neuronal plasticity. We tested the hypothesis that plastic processes during wake lead to a net increase in synaptic strength and sleep is necessary for synaptic renormalization. We found that, in three Drosophila neuronal circuits, synapse size or number increases after a few hours of wake and decreases only if flies are allowed to sleep. A richer wake experience resulted in both larger synaptic growth and greater sleep need. Finally, we demonstrate that the gene Fmr1 (fragile X mental retardation 1) plays an important role in sleep-dependent synaptic renormalization.

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    • "Previous studies linked defective synaptic plasticity mechanisms to sleep need in Drosophila (Bushey, Tononi, and Cirelli 2011; Ganguly-Fitzgerald, Donlea, and Shaw 2006; J. M. Donlea, Ramanan, and Shaw 2009), leading us to investigate sleep patterns in dnrx1 knockout male and female flies (Figure 1d). Compared to WT flies, dnrx1 knockouts (313/241 and 273/313) display perturbed sleep patterns, most obviously as they sleep more at dusk (Figure 1d). "
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    ABSTRACT: Neurexins are cell adhesion molecules important for synaptic plasticity and homeostasis, though links to sleep have not yet been investigated. We examined effects of neurexin-1 perturbation on sleep in Drosophila, showing that neurexin-1 nulls display fragmented sleep and altered circadian rhythm. Conversely, over-expression of neurexin-1 can increase and consolidate night-time sleep. This is not solely due to developmental effects as it can be induced acutely in adulthood, and is coupled with evidence for synaptic growth. Timing of over-expression can differentially impact sleep patterns, with specific night-time effects. These results show that neurexin-1 is dynamically involved in synaptic plasticity and sleep in Drosophila. Neurexin-1 and a number of its binding partners have been repeatedly associated with mental health disorders, including autism spectrum disorders, schizophrenia and Tourette syndrome, all of which are also linked to altered sleep patterns. How and when plasticity-related proteins such as neurexin-1 function during sleep can provide vital information on the interaction between synaptic homeostasis and sleep, paving the way for more informed treatments of human disorders. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Neuroscience 07/2015; 42(7). DOI:10.1111/ejn.13023 · 3.18 Impact Factor
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    • "Another study detected a downregulation of GluR1-containing AMPA receptor (AMPAR) levels during sleep, as well as a decrease in the phosphorylation of AMPARs, CamKII and GSK3beta (Vyazovskiy & et al., 2008). In Drosophila, sleep has been associated with a decrease in the number and size of synapses (Bushey, Tononi, & Cirelli, 2011). These findings support the Synaptic Homeostasis Hypothesis (SHY), which postulates that wakefulness and sleep are respectively associated with a net increase and decrease in synaptic strength (Tononi & Cirelli, 2003, 2012). "
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    ABSTRACT: Sleep is beneficial to learning, but the underlying mechanisms remain controversial. The synaptic homeostasis hypothesis (SHY) proposes that the cognitive function of sleep is related to a generalized rescaling of synaptic weights to intermediate levels, due to a passive downregulation of plasticity mechanisms. A competing hypothesis proposes that the active upscaling and downscaling of synaptic weights during sleep embosses memories in circuits respectively activated or deactivated during prior waking experience, leading to memory changes beyond rescaling. Both theories have empirical support but the experimental designs underlying the conflicting studies are not congruent, therefore a consensus is yet to be reached. To advance this issue, we used real-time PCR and electrophysiological recordings to assess gene expression related to synaptic plasticity in the hippocampus and primary somatosensory cortex of rats exposed to novel objects, then kept awake (WK) for 60 min and finally killed after a 30 min period rich in WK, slow-wave sleep (SWS) or rapid-eye-movement sleep (REM). Animals similarly treated but not exposed to novel objects were used as controls. We found that the mRNA levels of Arc, Egr1, Fos, Ppp2ca and Ppp2r2d were significantly increased in the hippocampus of exposed animals allowed to enter REM, in comparison with control animals. Experience-dependent changes during sleep were not significant in the hippocampus for Bdnf, Camk4, Creb1, and Nr4a1, and no differences were detected between exposed and control SWS groups for any of the genes tested. No significant changes in gene expression were detected in the primary somatosensory cortex during sleep, in contrast with previous studies using longer post-stimulation intervals (>180 min). The experience-dependent induction of multiple plasticity-related genes in the hippocampus during early REM adds experimental support to the synaptic embossing theory.
    Neurobiology of Learning and Memory 01/2015; 93. DOI:10.1016/j.nlm.2015.01.002 · 3.65 Impact Factor
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    • "In insects, detailed studies of sleep have been performed in many species including cockroaches, bees, mosquitoes and Drosophila (Tobler, 1983; Tobler and Neuner-Jehle, 1992; Hendricks et al., 2000; Shaw et al., 2000; Eban-Rothschild and Bloch, 2008; Klein et al., 2008; Bushey et al., 2011). Over the past 15 years, our understanding of the functions of sleep and its functional necessity has rapidly progressed through research in Drosophila (reviewed in Cirelli and Tononi, 2008; Piscopo, 2009; Potdar and Sheeba, 2013) by providing evidence for the synaptic homeostasis hypothesis of sleep proposed by Tononi and Cirelli (2003). "
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    ABSTRACT: Across phylogeny, the endogenous biological clock has been recognized as providing adaptive advantages to organisms through coordination of physiological and behavioral processes. Recent research has emphasized the role of circadian modulation of memory in generating peaks and troughs in cognitive performance. The circadian clock along with homeostatic processes also regulates sleep, which itself impacts the formation and consolidation of memory. Thus, the circadian clock, sleep and memory form a triad with ongoing dynamic interactions. With technological advances and the development of a global 24/7 society, understanding the mechanisms underlying these connections becomes pivotal for development of therapeutic treatments for memory disorders and to address issues in cognitive performance arising from non-traditional work schedules. Invertebrate models, such as Drosophila melanogaster and the mollusks Aplysia and Lymnaea, have proven invaluable tools for identification of highly conserved molecular processes in memory. Recent research from invertebrate systems has outlined the influence of sleep and the circadian clock upon synaptic plasticity. In this review, we discuss the effects of the circadian clock and sleep on memory formation in invertebrates drawing attention to the potential of in vivo and in vitro approaches that harness the power of simple invertebrate systems to correlate individual cellular processes with complex behaviors. In conclusion, this review highlights how studies in invertebrates with relatively simple nervous systems can provide mechanistic insights into corresponding behaviors in higher organisms and can be used to outline possible therapeutic options to guide further targeted inquiry.
    Frontiers in Systems Neuroscience 08/2014; 8:133. DOI:10.3389/fnsys.2014.00133
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