Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice

Gu, Bin; Zhu, Manhua; Glass, Madison R.; Rougié, Marie; Nikolova, Viktoriya D.; Moy, Sheryl S.; Carney, Paul R.; Philpot, Benjamin D.

doi:10.1172/jci130419

Cited by 42 publications

(29 citation statements)

References 45 publications

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“…Thibert and Anderson have carefully explained their reports of elevated delta power in AS clinics [31,32]. Further, we reproduced Sidorov et al earlier work [46] that highlighted delta power as translational biomarker [31,33]. This phenotypic reliability paves the pathway to power spectral signatures as therapeutic windows for precision treatment within AS and beyond including other NDDs, such as Dup15q and genetic forms of ASD [47][48][49][50].…”

Section: Discussionsupporting

confidence: 68%

“…Many laboratories have used this AS mouse model of Jiang and Beaduet [11] and reported numerous characteristics that resemble core features of AS including seizure susceptibility, increased epileptiform activity, elevated delta and sleep de cits, though they vary widely on seizure induction methods, background strain and EEG collection techniques [15,[27][28][29][30][31][32][33]. In corroboration and extension, we quanti ed seizure susceptibility in Ube3a-del mice on the seizure resistant C57BL/6J background strain instead of the 129S1/SvImJ often used for seizure studies in AS, since the C57BL/6J's are resistant to seizures [34].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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

Copping

Silverman

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…[31,32]. Further, we reproduced Sidorov et al earlier work [45] that highlighted delta power as translational biomarker [31,33]. This phenotypic reliability paves the pathway to power spectral signatures as therapeutic windows for precision treatment within AS and beyond including other NDDs, such as Dup15q and genetic forms of ASD [46][47][48][49].…”

Section: Discussionsupporting

confidence: 64%

“…Many laboratories have used this AS mouse model of Jiang and Beaduet [11] and reported numerous characteristics that resemble core features of AS including seizure susceptibility, increased epileptiform activity, elevated delta and sleep deficits, though they vary widely on seizure induction methods, background strain and EEG collection techniques [15,[27][28][29][30][31][32][33]. In corroboration and extension, we quantified seizure susceptibility in Ube3a-del mice on the seizure resistant C57BL/6J background strain versus the seizure prone 129S1/SvImJ [34].…”

Section: Introductionmentioning

confidence: 88%

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

Copping

Silverman

2020

Preprint

View full text Add to dashboard Cite

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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“…Gu and colleagues, using a mouse model of Angelman syndrome, a neurodevelopmental disorder characterized by cognitive impairment, lack of speech, ataxia, EEG abnormalities, and pharmaco-resistant epilepsy, were able to significantly reduce hyperthermia-and acoustically induced seizures, with a reduction of epileptic activity in EEG recordings. Furthermore, CBD application strongly reduced the theta and delta EEG rhythms that are typical in this condition, without any sign of motor activity impairment [93]. However, further studies are needed to better explain the effect of CBD administration in these pathological conditions.…”

Section: Epilepsymentioning

confidence: 84%

Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

Cifelli

Ruffolo

Felice

et al. 2020

IJMS

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γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs.

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Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice

Cited by 42 publications

References 45 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

Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

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