Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome

Godavarthi, Swetha K.; Dey, Partha Narayan; Sharma, Ankit; Jana, Nihar Ranjan

doi:10.1016/j.bbrc.2015.07.103

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…They provided evidence that the AS genotype did not affect proliferation nor the survival of hippocampal neurons; however, the percentage of newborn cells with neuronal phenotype was significantly reduced, pointing out a possible impairment in neurogenesis. Indeed, the impairment of adult neurogenesis was shown by Godavarthi and collaborators, who described a decrease in BrdU + and Ki67 + proliferative cells, along with decreased DCX + immature neurons in the hippocampal DG region of adult AS mice . The increased severity of neurogenesis impairment seen in this work can be explained by the total loss of UBE3A function in AS mice compared with the partial loss of only the ubiquitin ligase domain in the first study.…”

Section: Molecular Pathogenesis: the Contribution Of The Hippocampussupporting

confidence: 62%

“…However, since the UBE3A protein is also expressed in neural progenitors, the negative effect of this mutation on neurogenesis should be non‐cell‐autonomous. The authors hypothesize that the loss of UBE3A might lead to increased stress levels in hippocampi of these mice, explaining why the impairment of neurogenesis is only seen at the adult stage .…”

Section: Molecular Pathogenesis: the Contribution Of The Hippocampusmentioning

confidence: 99%

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Angelman syndrome: a journey through the brain

et al. 2020

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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.

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Section: Molecular Pathogenesis: the Contribution Of The Hippocampussupporting

confidence: 62%

Section: Molecular Pathogenesis: the Contribution Of The Hippocampusmentioning

confidence: 99%

Angelman syndrome: a journey through the brain

et al. 2020

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“…Fluoxetine, a serotonin selective reuptake inhibitor (SSRI), has been found to block all three SK channels in vitro [Terstappen et al, ]. Treatment of adult AS mice with subcutaneous fluoxetine partially restored hippocampal neurogenesis, but learning and behavioral assays were not reported for these fluoxetine‐treated mice [Godavarthi et al, ], and there are no reports on the outcome of any individual with AS who has received fluoxetine.…”

Section: Resultsmentioning

confidence: 99%

Angelman syndrome: Current and emerging therapies in 2016

Tan¹,

Bird²

2016

American J of Med Genetics Pt C

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Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally-inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS) at the unmethylated paternal locus. We reviewed all published information on the clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies in AS. To date, all clinical trials that strove to improve neurodevelopment in AS have been unsuccessful. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of an 8-week open-label trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive, while a subsequent randomized placebo-controlled trial suggested that treatment with minocycline for 8 weeks did not result in any neurodevelopmental gains. A 1-year randomized placebo-controlled trial using levodopa to alter the phosphorylation of calcium/calmodulin-dependent kinase II did not lead to any improvement in neurodevelopment. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A-AS. Artificial transcription factors are being developed to "super activate" UBE3A or inhibit UBE3A-AS. Other strategies targeting specific pathways are briefly discussed. We also reviewed the medications that are currently used to treat seizures and sleep disturbances, which are two of the more common complications of AS. © 2016 Wiley Periodicals, Inc.

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“…The expression of both BDNF and glucocorticoid receptor is decreased in AS mice, which may cause the reduced number of parvalbumin‐positive interneurons in the hippocampus (Godavarthi, Dey, Maheshwari, & Ranjan, ). Administration of fluoxetine rescued neurogenesis in AS mice (Godavarthi, Dey, Sharma, & Jana, ; Godavarthi, Sharma, & Jana, ).…”

Section: Ube3a Signaling Pathwaysmentioning

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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Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome

Cited by 15 publications

References 36 publications

Angelman syndrome: a journey through the brain

Angelman syndrome: a journey through the brain

Angelman syndrome: Current and emerging therapies in 2016

Towards an understanding of Angelman syndrome in mice studies

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