Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model

Ciarlone, Stephanie L.; Wang, Xinming; Rogawski, Michael A.; Weeber, Edwin J.

doi:10.1016/j.neuropharm.2016.12.009

Cited by 36 publications

(33 citation statements)

References 49 publications

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“…While the foregoing genes are likely crucial to the presence of the beta EEG phenotype [5], UBE3A plays a critical role in the development and function of GABAergic circuits, including neurons that co-release GABA in rodents [28,29], suggesting that it also affects beta oscillations. As further evidence of the intimate connection between UBE3A and GABA, the GABA A enhancers gaboxadol and ganaxolone have been shown to restore behavioral phenotypes in Ube3a knockout mice [30,31]. Thus, UBE3A overexpression likely affects GABAergic transmission in this syndrome.…”

Section: Introductionmentioning

confidence: 98%

Properties of beta oscillations in Dup15q syndrome

Saravanapandian

Frohlich

Hipp

et al. 2020

J Neurodevelop Disord

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Background: Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism, intellectual disability, hypotonia, and epilepsy. The 15q region harbors genes critical for brain development, particularly UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABA A R) genes. We recently described an electrophysiological biomarker of the syndrome, characterized by excessive beta oscillations (12-30 Hz), resembling electroencephalogram (EEG) changes induced by allosteric modulation of GABA A Rs. In this follow-up study, we tested a larger cohort of children with Dup15q syndrome to comprehensively examine properties of this EEG biomarker that would inform its use in future clinical trials, specifically, its (1) relation to basic clinical features, such as age, duplication type, and epilepsy; (2) relation to behavioral characteristics, such as cognition and adaptive function; (3) stability over time; and (4) reproducibility of the signal in clinical EEG recordings. Methods: We computed EEG power and beta peak frequency (BPF) in a cohort of children with Dup15q syndrome (N = 41, age range 9-189 months). To relate EEG parameters to clinical (study 1) and behavioral features (study 2), we examined age, duplication type, epilepsy, cognition, and daily living skills (DLS) as predictors of beta power and BPF. To evaluate stability over time (study 3), we derived the intraclass correlation coefficients (ICC) from beta power and BPF computed from children with multiple EEG recordings (N = 10, age range 18-161 months). To evaluate reproducibility in a clinical setting (study 4), we derived ICCs from beta power computed from children (N = 8, age range 19-96 months), who had undergone both research EEG and clinical EEG. Results: The most promising relationships between EEG and clinical traits were found using BPF. BPF was predicted both by epilepsy status (R 2 = 0.11, p = 0.038) and the DLS component of the Vineland Adaptive Behavior Scale (R 2 = 0.17, p = 0.01). Beta power and peak frequency showed high stability across repeated visits (beta power ICC = 0.93, BPF ICC = 0.92). A reproducibility analysis revealed that beta power estimates are comparable between research and clinical EEG (ICC = 0.94).

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Section: Introductionmentioning

confidence: 98%

Properties of beta oscillations in Dup15q syndrome

Saravanapandian

Frohlich

Hipp

et al. 2020

J Neurodevelop Disord

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“…Hence, the administration of THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol), a selective extra‐synaptic GABAA receptor agonist, improved neuronal properties and reduced cerebellar ataxia in AS mice (Egawa et al, ). Accordingly, the synthetic neurosteroid ganaxolone was also effective in controlling seizures after long‐term treatment (Ciarlone, Wang, Rogawski, & Weeber, ). Inspired by the success of the ketogenic diet in controlling epilepsy, ketone ester was found to be beneficial in controlling seizure and improve LTP and memory in a mouse model of AS (Ciarlone et al, ).…”

Section: As Mouse Models Inspired Potential Treatmentsmentioning

confidence: 99%

Towards an understanding of Angelman syndrome in mice studies

Yang

2019

J of Neuroscience Research

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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.

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“…But the caveat is the severer mental retardation is not well reproduced in AS mice (Sonzogni et al., 2018) and the adult expressed Ube3a is not enough for the functional recovery on behaviors (Huang et al., 2012; Meng et al., 2015; Silva‐Santos et al, 2015). Since the success of rescuing neuronal electrophysiological properties (Rotaru, van Woerden, Wallaard, & Elgersma, 2018), synaptic plasticity like LTP, and learning and memory(Ciarlone, Grieco, D’Agostino, & Weeber, 2016; Ciarlone, Wang, Rogawski, & Weeber, 2017; Kaphzan et al., 2012; Sun et al., 2016, 2018; Sun, Zhu, et al, 2015; van Woerden et al., 2007), it is possible to develop interventions and treatments for AS.…”

Section: Introductionmentioning

confidence: 99%

Characterizing spine issues: If offers novel therapeutics to Angelman syndrome

Yang

2020

Developmental Neurobiology

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Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe mental retardation, microcephaly, speech impairment, frequent epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, bursts of laughter, sleep abruptions, and hyperactivity. AS results from loss of function of the imprinted UBE3A (ubiquitin‐protein ligase E3A) gene on chromosome 15q11–q13, including a mutation on the maternal allele of Ube3a, a large deletion of the maternally inherited chromosomal region 15q11–13, paternal uniparental disomy of chromosome 15q11–13, or an imprinting defect. The Ube3a maternal deleted mouse model recaptured the major phenotypes of AS patients include seizure, learning and memory impairments, sleep disturbance, and motor problems. Owing to the activity‐dependent structural and functional plasticity, dendritic spines are believed as the basic subcellular compartment for learning and memory and the sites where LTP and LTD are induced. Defects of spine formation and dynamics are common among several neurodevelopmental disorders and neuropsychiatric disorders including AS and reflect the underlying synaptopathology, which drives clinically relevant behavioral deficits. This review will summarize the impaired spine density, morphology, and synaptic plasticity in AS and propose that future explorations on spine dynamics and synaptic plasticity may help develop novel interventions and therapy for neurodevelopmental disorders like AS.

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Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model

Cited by 36 publications

References 49 publications

Properties of beta oscillations in Dup15q syndrome

Properties of beta oscillations in Dup15q syndrome

Towards an understanding of Angelman syndrome in mice studies

Characterizing spine issues: If offers novel therapeutics to Angelman syndrome

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