Modeling genetic epilepsies in a dish

Niu, Wei; Parent, Jack M.

doi:10.1002/dvdy.79

Cited by 32 publications

(25 citation statements)

References 240 publications

(365 reference statements)

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“…Importantly, our results highlight the translational potential of COs to model neurodevelopmental disorders that arise from aberrant neural network formation. To date, COs have provided critical insights into the structural etiology of several neurodevelopmental disorders, including autism ( Hou et al., 2020 ; Mariani et al., 2015 ; Papariello and Newell-Litwa, 2020 ; Wang et al., 2020 ; Zhang et al., 2020 ) and epilepsy ( Niu and Parent, 2020 ; Sun et al., 2019 ). However, the characterization of neural network activity is indispensable in several of these disorders, including epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Maturation of Cerebral Organoids Correlates with Dynamic Morphological and Cellular Development

et al. 2020

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Summary Cerebral organoids (COs) are rapidly accelerating the rate of translational neuroscience based on their potential to model complex features of the developing human brain. Several studies have examined the electrophysiological and neural network features of COs; however, no study has comprehensively investigated the developmental trajectory of electrophysiological properties in whole-brain COs and correlated these properties with developmentally linked morphological and cellular features. Here, we profiled the neuroelectrical activities of COs over the span of 5 months with a multi-electrode array platform and observed the emergence and maturation of several electrophysiologic properties, including rapid firing rates and network bursting events. To complement these analyses, we characterized the complex molecular and cellular development that gives rise to these mature neuroelectrical properties with immunohistochemical and single-cell transcriptomic analyses. This integrated approach highlights the value of COs as an emerging model system of human brain development and neurological disease.

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Section: Discussionmentioning

confidence: 99%

Electrophysiological Maturation of Cerebral Organoids Correlates with Dynamic Morphological and Cellular Development

et al. 2020

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“…Homozygous, but not heterozygous, loss of TSC1 or TSC2 disrupts the developmental suppression of mTORC1 signaling providing strong support for the two-hit hypothesis of TSC pathophysiology. They also showed that early rapamycin treatment of the brain organoids prevented development of the abnormal phenotypes ( Blair et al, 2018 ; Niu and Parent, 2019 ).…”

Section: Brain Organoids and Epilepsymentioning

confidence: 97%

Brain Organoids as Model Systems for Genetic Neurodevelopmental Disorders

Baldassari

Musante

Iacomino

et al. 2020

Front. Cell Dev. Biol.

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Neurodevelopmental disorders (NDDs) are a group of disorders in which the development of the central nervous system (CNS) is disturbed, resulting in different neurological and neuropsychiatric features, such as impaired motor function, learning, language or non-verbal communication. Frequent comorbidities include epilepsy and movement disorders. Advances in DNA sequencing technologies revealed identifiable genetic causes in an increasingly large proportion of NDDs, highlighting the need of experimental approaches to investigate the defective genes and the molecular pathways implicated in abnormal brain development. However, targeted approaches to investigate specific molecular defects and their implications in human brain dysfunction are prevented by limited access to patient-derived brain tissues. In this context, advances of both stem cell technologies and genome editing strategies during the last decade led to the generation of three-dimensional (3D) in vitro -models of cerebral organoids, holding the potential to recapitulate precise stages of human brain development with the aim of personalized diagnostic and therapeutic approaches. Recent progresses allowed to generate 3D-structures of both neuronal and non-neuronal cell types and develop either whole-brain or region-specific cerebral organoids in order to investigate in vitro key brain developmental processes, such as neuronal cell morphogenesis, migration and connectivity. In this review, we summarized emerging methodological approaches in the field of brain organoid technologies and their application to dissect disease mechanisms underlying an array of pediatric brain developmental disorders, with a particular focus on autism spectrum disorders (ASDs) and epileptic encephalopathies.

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“…technology (Niu & Parent, 2020). hiPSCs allow to model disease by generating neuronal cells that carry the specific genetic information of the patient and to test gene therapies in the context of the human genome, which could improve translational success (Zhao & Bhattacharyya, 2018).…”

Section: In Vitro Human Models Of Ndd + Ementioning

confidence: 99%