mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex

Kelly, Elyza; Schaeffer, Samantha M; Dhamne, Sameer C.; Lipton, Jonathan O.; Lindemann, Lothar; Honer, Michael; Jaeschke, Georg; Super, Chloe E.; Lammers, Stephen H.T.; Modi, Meera E.; Silverman, Jill L.; Dreier, John R.; Kwiatkowski, David J.; Rotenberg, Alexander; Şahin, Mustafa

doi:10.1038/npp.2017.295

Cited by 38 publications

(57 citation statements)

References 29 publications

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“…b, Coordinate regulation of REST and FOXO1 in human prefrontal cortex. Nuclear REST and FOXO1 protein levels were determined by immunofluorescence microscopy in pyramidal neurons of the prefrontal cortex in individual young adult (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)…”

Section: Extended Datamentioning

confidence: 99%

Regulation of lifespan by neural excitation and REST

Zullo

Drake

Aron

et al. 2019

Nature

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185

164

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The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex characterized by downregulation of genes related to neural excitation and synaptic function. In the model system C. elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The REST transcription factor is upregulated in humans with extended longevity and represses excitationrelated genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during aging. Similarly, loss-of-function mutations in the C. elegans REST orthologs Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Extended Datamentioning

confidence: 99%

Regulation of lifespan by neural excitation and REST

Zullo

Drake

Aron

et al. 2019

Nature

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185

164

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“…Under isoflurane, mice were intraperitoneally implanted with wireless telemetry transmitters (PhysioTel ETA-F10; DSI, Data Sciences International, St. Paul, MN) using skull screws by threading the electrodes to the cranial cavity per laboratory protocol [1,2]. After analgesia and a week of recovery, mice were individually housed in transparent home cages in a 12 h light (7am-7pm)/12 h dark (7pm-7am), temperature, and humidity-controlled chamber with ad libitum access to food and water.…”

Section: Eeg Data Acquisitionmentioning

confidence: 99%

“…Translational epilepsy studies often employ rodent models whose phenotypes recapitulate human disease. In particular, mouse EEG recorded by skull screw electrodes is a valuable tool for phenotypic characterization and for drug discovery [1,2]. Among the range of signals and metrics that can be derived from mouse EEGs are spikes and sharp waves, occurring individually or in 'runs', that closely resemble epileptiform discharges observed in humans with epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Electrographic spikes are common in wildtype mice

Purtell

Dhamne

Gurnani

et al. 2018

Epilepsy & Behavior

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High-voltage rhythmic EEG spikes have been recorded in wildtype (WT) rats during periods of light slow-wave sleep and passive wakefulness. The source of this activity is unclear, but has been attributed to either an inherent form of absence epilepsy or a normal feature of rodent sleep EEG. In contrast, little is known about epileptiform spikes in WT mice. We thus characterize and quantify epileptiform discharges in WT mice for the first time. 24-hour wireless telemetry video-EEG recordings in 36 male WT C57 mice were manually scored by blinded reviewers to mark individual spikes and spike trains. Epileptiform spikes were detected in 100% of the recorded WT mice, and spike trains of at least three spikes were recorded in 90% of mice. The spikes were more frequent during the day than at night, and were inversely correlated to each animal's locomotor activity. However, the discharges were not absent during active nighttime periods. These discharges may indicate a baseline tendency toward epileptic seizures, or perhaps are benign variants of normal rodent background EEG. Regardless, a better understanding of baseline WT EEG activity will aid in differentiating pathological and normal EEG activity in mouse epilepsy models.

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“…While we and others have previously described behavioral deficits in rodent models of AS [16,17] and other neurodevelopmental disorders (NDDs) [18][19][20][21][22][23][24][25][26], an effort has been made to incorporate in vivo electrophysiology, expanding clinically analogous phenotypes that can be provided as proof of in vivo efficacy. Pursuant to this goal we sought to identify relevant functional phenotypes, including seizures, EEG signature, sleep patterns and sleep spindles using the most rigorously characterized mouse model of AS, with a deletion of Ube3a (Ube3a-del) inherited from the maternal allele resulting in Ube3am-/p+ on the C57BL/6J background generated from breeding Ube3am+/p-females with Ube3am+/p+ males [11].…”

Section: Introductionmentioning

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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mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex

Cited by 38 publications

References 29 publications

Regulation of lifespan by neural excitation and REST

Regulation of lifespan by neural excitation and REST

Electrographic spikes are common in wildtype mice

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

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