Shank3 modulates sleep and expression of circadian transcription factors

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

doi:10.7554/elife.42819

Cited by 66 publications

(76 citation statements)

References 85 publications

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“…A disruption in excitation/inhibition balance may also alter network properties such as brain rhythms. Indeed, altered EEG rhythms, including an increase in gamma power, have been observed in Shank3 -mutant mice (Han et al, 2013; Wang et al, 2016; Dhamne et al, 2017; Ingiosi et al, 2019; Yoo et al, 2019) as well as in SHANK3 -related ASD and PMS (Soorya et al, 2013; Holder and Quach, 2016).…”

Section: Discussionmentioning

confidence: 99%

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Yoo

Cho

Park

et al. 2019

Front. Cell. Neurosci.

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Shank3, an abundant excitatory postsynaptic scaffolding protein, has been associated with multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). However, how cell type-specific Shank3 deletion affects disease-related neuronal and brain functions remains largely unclear. Here, we investigated the impacts of Shank3 deletion in glutamatergic neurons on synaptic and behavioral phenotypes in mice and compared results with those previously obtained from mice with global Shank3 mutation and GABAergic neuron-specific Shank3 mutation. Neuronal excitability was abnormally increased in layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC) in mice with a glutamatergic Shank3 deletion, similar to results obtained in mice with a global Shank3 deletion. In addition, excitatory synaptic transmission was abnormally increased in layer 2/3 neurons in mice with a global, but not a glutamatergic, Shank3 deletion, suggesting that Shank3 in glutamatergic neurons are important for the increased neuronal excitability, but not for the increased excitatory synaptic transmission. Neither excitatory nor inhibitory synaptic transmission was altered in the dorsal striatum of Shank3-deficient glutamatergic neurons, a finding that contrasts with the decreased excitatory synaptic transmission in global and Shank3-deficient GABAergic neurons. Behaviorally, glutamatergic Shank3-deficient mice displayed abnormally increased direct social interaction and repetitive self-grooming, similar to global and GABAergic Shank3-deficient mice. These results suggest that glutamatergic and GABAergic Shank3 deletions lead to distinct synaptic and neuronal changes in cortical layer 2/3 and dorsal striatal neurons, but cause similar social and repetitive behavioral abnormalities likely through distinct mechanisms.

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Section: Discussionmentioning

confidence: 99%

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Yoo

Cho

Park

et al. 2019

Front. Cell. Neurosci.

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“…The hippocampus appears particularly susceptible to the effects of acute sleep deprivation with sleep deprivation affecting gene expression, kinase signaling pathways, spatial memory consolidation, synaptic plasticity and neuronal structure [10][11][12][13][14][15][16][17]. The hippocampus is not the only brain region affected by sleep deprivation, as studies of the cortex and forebrain also reported changes in gene expression after sleep deprivation [18][19][20][21]. Despite the widespread transcriptional changes induced by sleep deprivation and the severity of the impact on memory, the mechanisms by which sleep deprivation adversely impairs neuronal function have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Translational changes induced by acute sleep deprivation uncovered by TRAP-Seq

et al. 2020

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Sleep deprivation is a global health problem adversely affecting health as well as causing decrements in learning and performance. Sleep deprivation induces significant changes in gene transcription in many brain regions, with the hippocampus particularly susceptible to acute sleep deprivation. However, less is known about the impacts of sleep deprivation on post-transcriptional gene regulation. To identify the effects of sleep deprivation on the translatome, we took advantage of the RiboTag mouse line to express HA-labeled Rpl22 in CaMKIIα neurons to selectively isolate and sequence mRNA transcripts associated with ribosomes in excitatory neurons. We found 198 differentially expressed genes in the ribosome-associated mRNA subset after sleep deprivation. In comparison with previously published data on gene expression in the hippocampus after sleep deprivation, we found that the subset of genes affected by sleep deprivation was considerably different in the translatome compared with the transcriptome, with only 49 genes regulated similarly. Interestingly, we found 478 genes differentially regulated by sleep deprivation in the transcriptome that were not significantly regulated in the translatome of excitatory neurons. Conversely, there were 149 genes differentially regulated by sleep deprivation in the translatome but not in the whole transcriptome. Pathway analysis revealed differences in the biological functions of genes exclusively regulated in the transcriptome or translatome, with protein deacetylase activity and small GTPase binding regulated in the transcriptome and unfolded protein binding, kinase inhibitor activity, neurotransmitter receptors and circadian rhythms regulated in the translatome. These results indicate that sleep deprivation induces significant changes affecting the pool of actively translated mRNAs.

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“…Sleep analysis is highly Ube3am-/p+ exhibited less spindles, as we hypothesized given the reduction in sleep spindles observed clinically in AS [43]. Fewer, abnormal sleep spindles have been historically implicated in intellectual disabilities [55,56] and for numerous genetic NDDs, such as Phelan-McDermid and Prader-Willi syndromes [57,58] as well as childhood epilepsies [59] [60] and ASDs [61,62]. Sleep spindles have been reported altered when mGluR5 is deficient [63], mGluR5 dysregulation has been postulated as underlying Fragile X Syndrome phenotypes, another NDD with ASD and poor sleep regulation [64,65].…”

Section: Discussionmentioning

confidence: 95%

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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Shank3 modulates sleep and expression of circadian transcription factors

Cited by 66 publications

References 85 publications

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Translational changes induced by acute sleep deprivation uncovered by TRAP-Seq

Abnormal Electrophysiological Phenotypes and Sleep Deficits in a Mouse Model of Angelman Syndrome

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