Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice

Gu, Bin; Carstens, Kelly E.; Judson, Matthew C.; Dalton, Katherine A; Rougié, Marie; Clark, Ellen P.; Dudek, Serena M.; Philpot, Benjamin D.

doi:10.1172/jci120816

Cited by 46 publications

(64 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…once per day) immediately after completion of flurothyl kindling followed by a 2-week drug washout prior to the flurothyl retest (SupplementalFigure 1A). Consistent with our previous findings(8), vehicle-treated AS mice exhibited enhanced seizure susceptibility at flurothyl retest compared to WT mice (SupplementalFigures 1B and 1C). Moreover, the post-kindling CBD treatments failed to attenuate the enhanced seizure susceptibility measured in AS model mice at flurothyl retest (Supplemental…”

supporting

confidence: 91%

“…Among the elevated EEG spectrum, enhanced delta rhythm is a particularly reliable biomarker for AS (13). Here we found that two weeks of CBD administrations reduced wide spectral cortical electrophysiological activities, and normalized the delta (1-4 Hz) and theta (5)(6)(7)(8) This study lends critical support for using CBD to treat seizures, along with behavioral and EEG abnormalities in AS, and expands the potential beneficial spectrum of CBD.…”

Section: Resultssupporting

confidence: 62%

“…We recently implemented the flurothyl kindling and retest paradigm in AS model mice (C57BL/6J background), and found that AS model mice responded to both initial (day1) seizure induction and kindling (day1 -day8) similarly to WT mice, but they displayed a markedly increased sensitivity to flurothyl-induced seizure measured a month later at retest (day36) (8). Elevation of core body temperature also triggered convulsions in kindled AS but not WT mice, resembling the clinical observation that AS individuals are susceptible to febrile seizures with moderate increases in body temperature (3,4,8). To test whether the anticonvulsant effects of CBD are generalizable across different seizure induction paradigms, we treated flurothyl-kindled mice acutely with CBD (100 mg/kg) 1 hr prior to the flurothyl-or hyperthermia-stimuli ( Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…The frequency, severity, and pharmacological intractability of the seizures exacts a heavy toll on individuals with AS and their caregivers (3)(4)(5)(6). AS model mice lacking a functional maternal copy of the orthologous Ube3a gene (Ube3a m-/p+ ) phenocopy many clinical aspects of AS, including seizure susceptibility and EEG abnormalities, thereby offering a preclinical model for developing new therapeutics (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice

Zhu²,

Glass³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in AS individuals are often refractory to existing antiepileptic medications. Therefore, there is an unmet need for better seizure control, which could potentially improve other symptomatic domains such as cognitive function.Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has anti-seizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here we show that acute CBD (100 mg/kg) attenuated hyperthermia-and acoustically-induced seizures in a mouse model of AS. However, neither acute CBD nor a two-weeklong course of CBD administered immediately after a kindling protocol could halt the pro-epileptogenic plasticity observed in AS model mice. CBD had a mild sedative effect, but did not have a major impact on motor performance. CBD abrogated the enhanced delta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. Our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS, and will thus help guide the rational development of CBD as an AS adjunctive treatment.

show abstract

supporting

confidence: 91%

Section: Resultssupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice

Zhu²,

Glass³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…This AS imprinting defect mouse is the first mouse model to recapitulate obesity shown by some young AS patients. Besides these mouse models with constitutional deletions reproducing human defects, more sophisticated models based on conditional KOs, including those in specific neurons or models of UBE3A reinstatement, have been advanced to study UBE3A function at particular cellular/developmental stages that will be detailed in the next sections. Apart from mouse models, Lopez et al .…”

Section: Models To Study Asmentioning

confidence: 99%

Angelman syndrome: a journey through the brain

et al. 2020

View full text Add to dashboard Cite

Angelman syndrome (AS) is an incurable neurodevelopmental disease caused by loss of function of the maternally inherited UBE3A gene. AS is characterized by a defined set of symptoms, namely severe developmental delay, speech impairment, uncontrolled laughter, and ataxia. Current understanding of the pathophysiology of AS relies mostly on studies using the murine model of the disease, although alternative models based on patient-derived stem cells are now emerging. Here, we summarize the literature of the last decade concerning the three major brain areas that have been the subject of study in the context of AS: hippocampus, cortex, and the cerebellum. Our comprehensive analysis highlights the major phenotypes ascribed to the different brain areas. Moreover, we also discuss the major drawbacks of current models and point out future directions for research in the context of AS, which will hopefully lead us to an effective treatment of this condition in humans.

show abstract

Towards an understanding of Angelman syndrome in mice studies

Yang

2019

J of Neuroscience Research

View full text Add to dashboard Cite

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe mental retardation, absence of speech, abnormal motor coordination, abnormal EEG, and spontaneous seizure. AS is caused by a deficiency in the ubiquitin ligase E3A (Ube3a) gene product, known to play a dual role as both ubiquitin ligase and transcription coactivator. In AS animal models, multiple Ube3a substrates are accumulated in neurons. So far, studies in mouse models have either aimed at re‐expressing Ube3a or manipulating downstream signaling pathways. Reintroducing Ube3a in AS mice showed promising results but may have two caveats. First, it may cause an overdosage in the Ube3a expression, which in turn is known to contribute to autism spectrum disorders. Second, in mutation cases, the exogenous Ube3a may have to compete with the mutated endogenous form. Such two caveats left spaces for developing therapies or interventions directed to targets downstream Ube3a. Notably, Ube3a expression is dynamically regulated by neuronal activity and plays a crucial role in synaptic plasticity. The abnormal synaptic plasticity uncovered in AS mice has been frequently rescued, but circuits symptoms like seizure are resistant to treatment. Future investigations are needed to further clarify the function (s) of Ube3a during development. Here I reviewed the recently identified major Ube3a substrates and signaling pathways involved in AS pathology, the Ube3a expression, imprinting and evolution, the AS mouse models that have been generated and inspired therapeutic potentials, and finally proposed some future explorations to better understand the AS pathology.

show abstract

Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice

Cited by 46 publications

References 37 publications

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice

Angelman syndrome: a journey through the brain

Towards an understanding of Angelman syndrome in mice studies

Contact Info

Product

Resources

About