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:10.1101/689943

Cited by 6 publications

(11 citation statements)

References 41 publications

(66 reference statements)

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“…In agreement with previous studies [Gu et al, 2019; Sonzogni et al, 2018], Ube3a m−/p+ mice had a significant impairment in marble‐burying behavior relative to WT littermates: they spent much less time burying marbles and buried significantly fewer marbles. IGF‐2 injection 20 min before the marble‐burying test fully reversed this impairment.…”

Section: Resultssupporting

confidence: 92%

“…The only behavior that was found unaffected by either IGF‐2 or M6P treatment was the open field behavior, which was assessed using distance traveled and center crossing, a measure believed to reflect anxiety. Similarly to what was reported in previous studies [Born et al, 2017; Gu et al, 2019; Huang et al, 2013; Mandel‐Brehm et al, 2015; Sonzogni et al, 2018], we found that AS mice have deficits in the total distance traveled during open field but not in the time spent in the center or number of entries in the open field arena. In fact, only a trend toward less time spent in the center of the open field for AS relative to WT was observed.…”

Section: Discussionsupporting

confidence: 91%

“…We used Kruskal–Wallis to compare three or more groups on a dependent variable that is measured on an ordinal level. This statistical test has been used in previous publications with the same type of data sets [Forcelli, Kalikhman, & Gale, 2013; Gu et al, 2019]. The chi‐square test was used to compare the percent of seizures between two groups.…”

Section: Methodsmentioning

confidence: 99%

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CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

et al. 2020

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Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin‐like growth factor 2 (IGF‐2) and mannose‐6‐phosphate (M6P), ligands of two independent binding sites of the cation‐independent M6P/IGF‐2 receptor (CIM6P/IGF‐2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF‐2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y‐maze. IGF‐2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF‐2R is a promising approach for developing novel therapeutics for AS. Lay Summary There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3am−/p+, in this study we show that systemic administration of ligands of the cation independent mannose‐6‐phosphate receptor, also known as insulin‐like growth factor 2 receptor (CIM6P/IGF‐2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF‐2R may represent novel, potential therapeutic targets for AS.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

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CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

et al. 2020

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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%

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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Epilepsy in Angelman syndrome: A scoping review

Samanta

2021

Brain and Development

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Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80-90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity. The onset of epilepsy is most prevalent between 1 and 3 years of age; however, approximately 25% of patients developed epilepsy before one year of age. Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence. More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features. Seizures are frequently pharmacoresistant. Considering underlying prominent GABAergic dysfunction, clinicians had used AEDs that target GABAergic signaling such as valproate, phenobarbital, and clonazepam as first-line therapies for AS. However, due to the unfavorable side effect profile of these AEDs, a recent treatment approach involves priority use of levetiracetam, clobazam, topiramate, lamotrigine, ethosuximide, VNS, and carbohydrate-restricted diets. Besides symptomatic management, there has been recent progress to find a curative treatment with the following approaches: 1. Gene/protein replacement therapy (Adeno and lentiviral vector therapy to deliver a gene or secretory protein); 2. Activation of the intact but silent paternal copy of UBE3A (antisense oligonucleotide therapy and artificial transcription factors); and 3. Downstream therapies (OV101/gaboxadol, ketone supplement, novel compounds/peptides, anti-inflammatory/regenerative therapy).

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Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice

Cited by 6 publications

References 41 publications

CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

CIM6P/IGF‐2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

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

Epilepsy in Angelman syndrome: A scoping review

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