Alterations in sleep, sleep spindle, and EEG power in mGluR5 knockout mice

Aguilar, David D; Strecker, Robert E.; Basheer, Radhika; McNally, James M.

doi:10.1152/jn.00532.2019

Cited by 26 publications

(27 citation statements)

References 69 publications

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“…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 ], and mGluR5 dysregulation has been postulated as underlying Fragile X Syndrome phenotypes, another NDD with ASD and poor sleep regulation [ 64 , 65 ]. Interestingly, there was a significant negative correlation between spindles and delta power, where animals with higher delta power tended to have lower spindle counts.…”

Section: Discussionmentioning

confidence: 99%

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

Copping

Silverman

2021

Molecular Autism

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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, and 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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Section: Discussionmentioning

confidence: 99%

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

Copping

Silverman

2021

Molecular Autism

View full text Add to dashboard Cite

show abstract

“…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 de cient [63], mGluR5 dysregulation has been postulated as underlying Fragile X Syndrome phenotypes, another NDD with ASD and poor sleep regulation [64,65]. Interestingly, there was a signi cant negative correlation between spindles and delta power, where animals with higher delta power tended to have lower spindle counts.…”

Section: Discussionmentioning

confidence: 99%

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

Copping

Silverman

2021

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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“…Carvalho et al demonstrated that the cortex and striatum of mGluR5 −/− mice showed reduced number of neurons at 12 months of age and provided evidence that mGluR5 plays an important role in brain aging through modulating multiple cell types (8). Most recently, a study showed that mGluR5 −/− mice have some translationally relevant abnormalities associated with schizophrenia (24).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Gut Microbiota and Inflammatory Factors in mGluR5-Knockout Mice

et al. 2020

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Introduction: Accumulating evidence indicates that the glutamatergic system plays an important role in the development of depression. Notably, the antidepressant effect of metabotropic glutamate receptor 5 (mGluR5) modulation is inconsistent across studies. Here, we attempted to identify the involvement of the gut microbiota and inflammation in mGluR5 −/− mice. Methods: mGluR5 −/− mice and their wild-type littermates were used in our study. We used the open field (OF) and elevated plus maze (EPM) tests to assess anxiety-like behaviors, and we used the two-day forced swim test (FST) and tail suspension test (TST) to test despair-like behaviors. 16S rDNA was used to analyze the gut microbiota. Enzymelinked immunosorbent assays (ELISAs) were used to measure the levels of inflammatory factors. Western blotting was used to detect the levels of various proteins. Results: mGluR5 −/− mice had no significant increase or decrease of despair-like behavior in the absence of stress exposure. However, mGluR5 −/− mice exhibited despair-like behaviors following stress exposure. No significant changes in other glutamate receptors or representative synaptic proteins were detected in the prefrontal cortex (PFC) or hippocampus of mGluR5 −/− mice. Very similar bacterial groups were observed in mGluR5 −/− mice and wild-type controls. In addition, there was no significant difference in the a-diversity of the microbiota between mGluR5 −/− mice and wild-type controls. The levels of all measured cytokines (IL-1b, IL-2, IL-4, IL-6, IL-10, and TNF-a) did not change significantly in the PFCs or colons of mGluR5 −/− mice. Conclusion: In conclusion, we deduced that mGluR5 −/− mice are susceptible to despairlike behavior. The systemic knockout of mGluR5 did not affect the gut microbiota or inflammatory factors in mice.

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Alterations in sleep, sleep spindle, and EEG power in mGluR5 knockout mice

Cited by 26 publications

References 69 publications

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

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

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

Analysis of the Gut Microbiota and Inflammatory Factors in mGluR5-Knockout Mice

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