Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids

Gomes, Ana Rita; Fernandes, Tiago G.; Vaz, Sandra H.; Silva, Teresa P; Bekman, Evguenia; Xapelli, Sara; Duarte, Sofia; Ghazvini, Mehrnaz; Gribnau, Joost; Muotri, Alysson R.; Trujillo, Cleber A.; Sebastião, Ana M.; Cabral, Joaquim M. S.; Diogo, Maria Margarida

doi:10.3389/fcell.2020.610427

Cited by 57 publications

(46 citation statements)

References 67 publications

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“…We successfully established a music-based intervention model in RTT in vivo; however, the analysis of FNDC5/BDNF signaling pathways hinted at the complex nature of biological activity in brain tissue that the intervention may influence. Engibeerin cortical organoids from human-induced pluripotent stem cells (iPSCs), showing neurite undergrowth, neurite coalescence, and soma size of interneurons, have recently been used as an in vitro RTT model [51,52]. The biological response or the roles of FNDC5/BNDF pathways in an in vitro humanized RTT model upon different music-based interventions, such as magnitude and frequency (Hz) of music, warrant further investigations in the future.…”

Section: Discussionmentioning

confidence: 99%

Music-Based Intervention Ameliorates Mecp2-Loss-Mediated Sociability Repression in Mice through the Prefrontal Cortex FNDC5/BDNF Pathway

Hung

Chen

et al. 2021

IJMS

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Patients with Rett syndrome (RTT) show severe difficulties with communication, social withdrawl, and learning. Music-based interventions improve social interaction, communication skills, eye contact, and physical skills and reduce seizure frequency in patients with RTT. This study aimed to investigate the mechanism by which music-based interventions compromise sociability impairments in mecp2 null/y mice as an experimental RTT model. Male mecp2 null/y mice and wild-type mice (24 days old) were randomly divided into control, noise, and music-based intervention groups. Mice were exposed to music or noise for 6 h/day for 3 consecutive weeks. Behavioral patterns, including anxiety, spontaneous exploration, and sociability, were characterized using open-field and three-chamber tests. BDNF, TrkB receptor motif, and FNDC5 expression in the prefrontal cortex (PFC), hippocampus, basal ganglia, and amygdala were probed using RT-PCR or immunoblotting. mecp2 null/y mice showed less locomotion in an open field than wild-type mice. The social novelty rather than the sociability of these animals increased following a music-based intervention, suggesting that music influenced the mecp2-deletion-induced social interaction repression rather than motor deficit. Mechanically, the loss of BDNF signaling in the prefrontal cortex and hippocampal regions, but not in the basal ganglia and amygdala, was compromised following the music-based intervention in mecp2 null/y mice, whereas TrkB signaling was not significantly changed in either region. FNDC5 expression in the prefrontal cortex region in mecp2 null/y mice also increased following the music-based intervention. Collective evidence reveals that music-based interventions improve mecp2-loss-induced social dysfunction. BDNF and FNDC5 signaling in the prefrontal cortex region mediates the music-based-intervention promotion of social interactions. This study gives new insight into the mechanisms underlying the improvement of social behaviors in mice suffering from experimental Rett syndrome following a music-based intervention.

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Section: Discussionmentioning

confidence: 99%

Music-Based Intervention Ameliorates Mecp2-Loss-Mediated Sociability Repression in Mice through the Prefrontal Cortex FNDC5/BDNF Pathway

Hung

Chen

et al. 2021

IJMS

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“…The severity of the phenotypic alterations upon impaired FOXG1 expression correlated directly with the remaining dose of FOXG1 in the cells, emphasising that a well-balanced availability of the FOXG1 protein is critical for proper brain development and function [63]. But still, whereas Rett syndrome patient-derived hiPSCs were differentiated into organoids [64], [65], this experimental approach is thus far not reported for hiPSCs of FOXG1 patients. Overall, there are now opportunities for investigating FOXG1 syndrome in hiPSCs and different types of organoids, e.g.…”

Section: Human-based Models Of Foxg1 Syndrome and Functionmentioning

confidence: 99%

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

Akol¹,

Gather²,

Vogel³

2021

Preprint

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Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signalling pathways and transcription programs. Forkhead Box G1 (FOXG1) is one of the master regulators that plays fundamental roles in forebrain development, from the timing of neurogenesis to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as increased yield of information from high throughput omics opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems to highlight prospects of research and possible clinical interventions.

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“…Alterations in neuronal activity were measured using patch-clamp at 1.5 and 2.6 months (81 days), revealing a reduction in the firing frequency and abortive-like action potential in mature MeCP2 mutant neurons. The fusion of region-specific organoids from MGE and cortex revealed defective interneuron migration in MeCP2 mutant assembloids at day 41 (1.3 months) (fusion of assembloids occurred at day 13) (Gomes et al, 2020a). In the future, it will be important to expand the analysis of RTT assembloids to address how dysfunction of interneurons caused by MeCP2 mutation can interfere with circuitry formation and cortical functioning.…”

Section: Rett Syndromementioning

confidence: 99%

The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

et al. 2021

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Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.

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Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids

Cited by 57 publications

References 67 publications

Music-Based Intervention Ameliorates Mecp2-Loss-Mediated Sociability Repression in Mice through the Prefrontal Cortex FNDC5/BDNF Pathway

Music-Based Intervention Ameliorates Mecp2-Loss-Mediated Sociability Repression in Mice through the Prefrontal Cortex FNDC5/BDNF Pathway

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

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