Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

Ingiosi, Ashley M; Wintler, Taylor; Schoch, Hannah; Singletary, Kristan G.; Righelli, Dario; Roser, Leandro Gabriel; Risso, Davide; Frank, Marcos G.; Peixoto, Lucı́a

doi:10.1101/465799

Cited by 19 publications

(51 citation statements)

References 46 publications

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“…Our findings in Shank3 e4-9 KO mice showing a significant genotype x phase interaction suggest increased sleep in the active phase compared to control mice. Our results contrast with a recent EEG study of Shank3 ∆C KO mice in which reduced sleep duration in the active phase was reported [ 18 ]. The affected isoform of Shank3 differed in our study, suggesting that Shank3 may be involved in the regulation of sleep but in a complex manner.…”

Section: Discussioncontrasting

confidence: 99%

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Sleep Duration in Mouse Models of Neurodevelopmental Disorders

et al. 2020

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Sleep abnormalities are common in patients with neurodevelopmental disorders, and it is thought that deficits in sleep may contribute to the unfolding of symptoms in these disorders. Appreciating sleep abnormalities in neurodevelopmental disorders could be important for designing a treatment for these disorders. We studied sleep duration in three mouse models by means of home-cage monitoring: Tsc2+/− (tuberous sclerosis complex), oxytocin receptor (Oxtr) knockout (KO) (autism spectrum disorders), and Shank3 e4-9 KO (Phelan–McDermid syndrome). We studied both male and female mice, and data were analyzed to examine effects of both genotype and sex. In general, we found that female mice slept less than males regardless of genotype or phase. We did not find any differences in sleep duration in either Tsc2+/− or Oxtr KO mice, compared to controls. In Shank3 e4-9 KO mice, we found a statistically significant genotype x phase interaction (p = 0.002) with a trend that Shank3e4-9 KO mice regardless of sex slept more than control mice in the active phase. Our results have implications for the management of patients with Phelan–McDermid syndrome.

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Section: Discussioncontrasting

confidence: 99%

“…In patients with Phelan–McDermid syndrome, 25% have ASD and 90% may have sleep problems [ 17 ]. A recent study showed that Shank3 ∆C KO mice had decreased sleep duration in the active phase, difficulty with sleep rebound, and abnormal circadian rhythm [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Sleep Duration in Mouse Models of Neurodevelopmental Disorders

et al. 2020

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“…Spindle count was not in uenced by sleep stage alterations as there was no signi cant correlations between spindles and mean paradoxical sleep time, mean slow-wave sleep time, or total sleep time. Fewer sleep spindles have been implicated in intellectual disabilities [56,57] and for numerous genetic NDDs, such as Phelan-McDermid and Prader-Willi syndromes [58,59] as well as pediatric epilepsies [60] [61] and ASDs [62,63]. Sleep spindles were also altered by mGluR5 de ciency [64], mGluR5 dysregulation and have been postulated as an underlying mechanism of phenotypes in Fragile X Syndrome, another NDD with poor sleep regulation [65,66].…”

Section: Discussionmentioning

confidence: 99%

Abnormal electrophysiological phenotypes and sleep deficits in a mouse model of Angelman Syndrome

Copping

Silverman

2020

Preprint

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Background: Angelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal specific loss of expression of UBE3A (ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (>80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS. Methods: We used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported in Ube3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light-dark cycles, sleep stages and sleep spindles in Ube3a-del and WT mice. Results: Ube3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated that Ube3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages, and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model. Limitations: This study was limited to the exon 2 deletion mouse model, future work will investigate the rat model of AS, containing a complete Ube3a deletion and pair EEG with behavior. Conclusions: Our data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first-time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing.

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“…SFARI evidence scores categorize genes based on evidence supporting a gene's relevance to ASD risk. Categories defined by SFARI database are as follows: 1 (High Confidence), 2 (Strong Candidate), 3 (Suggestive Evidence), 4 (Minimal Evidence), 5 (Hypothesized), and S (Syndromic) (Diessler et al, 2017;Dudley et al, 2003;Ehlen et al, 2015;Han et al, 2012;Ingiosi et al, 2019;Jaaro-Peled et al, 2016;Kalume et al, 2015;Kozlov et al, 2007;Lacaria, Gu, & Lupski, 2013, p. 1;Li et al, 2015;Lipton et al, 2017;Meredith et al, 2006;Sahar, Nin, Barbosa, Chini, & Sassone-Corsi, 2011;Saré et al, 2017;Tsuchiya et al, 2015;Wither et al, 2012;Zhang et al, 2008;Zheng et al, 2001) (Seibt et al, 2012). Aberrant protein synthesis has been proposed as one of the molecular pathways leading to ASD (Kelleher & Bear, 2008 These findings suggest that sleep and circadian-regulating mechanisms involve a different but partially overlapping set of genes.…”

Section: Summary and Future D Irec Ti On Smentioning

confidence: 99%

“…Required parameters for sleep characterization are as follows: time in state (wake, NREMS and REMS, baseline and SD day), spectral power for each state (baseline and SD day), latency to sleep following SD, sleep fragmentation (number of bouts in each state per hours, baseline and SD). Standardized protocol adapted fromIngiosi et al (2019) [Color figure can be viewed at wileyonlinelibrary.com] plasticity in vivo…”

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confidence: 99%

Sleep, brain development, and autism spectrum disorders: Insights from animal models

Wintler

Schoch

Frank

et al. 2020

J of Neuroscience Research

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Sleep is an evolutionarily conserved and powerful drive, although its complete functions are still unknown. One possible function of sleep is that it promotes brain development. The amount of sleep is greatest during ages when the brain is rapidly developing, and sleep has been shown to influence critical period plasticity. This supports a role for sleep in brain development and suggests that abnormal sleep in early life may lead to abnormal development. Autism spectrum disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States. It is estimated that insomnia affects 44%–86% of the ASD population, predicting the severity of ASD core symptoms and associated behavioral problems. Sleep problems impact the quality of life of both ASD individuals and their caregivers, thus it is important to understand why they are so prevalent. In this review, we explore the role of sleep in early life as a causal factor in ASD. First, we review fundamental steps in mammalian sleep ontogeny and regulation and how sleep influences brain development. Next, we summarize current knowledge gained from studying sleep in animal models of ASD. Ultimately, our goal is to highlight the importance of understanding the role of sleep in brain development and the use of animal models to provide mechanistic insight into the origin of sleep problems in ASD.

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Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

Cited by 19 publications

References 46 publications

Sleep Duration in Mouse Models of Neurodevelopmental Disorders

Sleep Duration in Mouse Models of Neurodevelopmental Disorders

Abnormal electrophysiological phenotypes and sleep deficits in a mouse model of Angelman Syndrome

Sleep, brain development, and autism spectrum disorders: Insights from animal models

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