Generation of a Novel Rat Model of Angelman Syndrome with a Complete <i>Ube3a</i> Gene Deletion

Dodge, Andie; Peters, Melinda; Greene, Hayden E.; Dietrick, Clifton; Botelho, Robert; Chung, Diana; Willman, Jonathan; Nenninger, Austin W.; Ciarlone, Stephanie L.; Kamath, Siddharth G.; Houdek, Pia; Sumová, Alena; Anderson, Anne E.; Dindot, Scott V.; Berg, Elizabeth L.; O’Geen, Henriette; Segal, David J.; Silverman, Jill L.; Weeber, Edwin J.; Nash, Kevin

doi:10.1002/aur.2267

Cited by 29 publications

(53 citation statements)

References 39 publications

(74 reference statements)

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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 Ube3a m−/ p+ on the C57BL/6 J background generated from breeding Ube3a m+/p− females with Ube3a m+/p+ males [11].…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

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

Copping

Silverman

2021

Molecular Autism

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“…We recently published on the creation a novel AS rat model [Dodge et al, 2020], which has allowed for easier exploration of CSF for analysis due to the larger volumes that can be obtained. In our endeavors to find a potential biomarker, we are the first to identify that wild type rats, but not AS rats, have UBE3A present in their CSF (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…UBE3A maternal deletion AS rats, described previously [Dodge et al, 2020]. Heterozygous female rats were bred with wild type male rats to produce maternal‐deficient AS offspring and age matched wild type litter mate controls.…”

Section: Methodsmentioning

confidence: 99%

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Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity

Dodge

Willman

et al. 2021

Autism Research

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Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity‐dependent manner. Lay Summary Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity‐dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645–655. © 2021 International Society for Autism Research and Wiley Periodicals LLC

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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.

show abstract

Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion

Cited by 29 publications

References 39 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

Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity

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

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