Schizophrenia-associated<i>NRXN1</i>deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids

Sebastian, Rebecca; Jin, Kang; Pavon, Narciso; Bansal, Ruby; Potter, Andrew; Song, Yoonjae; Babu, Juliana; Gabriel, Rafael; Sun, Yubing; Aronow, Bruce J.; Pak, ChangHui

doi:10.1101/2022.08.24.505165

Cited by 4 publications

(4 citation statements)

References 119 publications

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“…4D). Though we observed a minor position variability in their neural activity, all three positions showed robust synchronous and spontaneous firing with expected metrics as previously published 60 . Hence, our results show free floating MIBOs that were cultured long-term out of the device yield active and viable organoids with mature neural network characteristics.…”

Section: Characterizing the Functioning Neural Circuits In Mibos Usin...supporting

confidence: 87%

Patterning ganglionic eminences in developing human brain organoids using morphogen gradient inducing device

Pavon,

Diep,

Yang

et al. 2023

Preprint

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In early neurodevelopment, the central nervous system is established through the coordination of various neural organizers directing tissue patterning and cell differentiation. Better recapitulation of morphogen gradient production and signaling will be crucial for establishing improved developmental models of the brain in vitro. Here, we developed a method by assembling polydimethylsiloxane (PDMS) devices capable of generating a sustained chemical gradient to produce patterned brain organoids, which we termed Morphogen-gradient Induced Brain Organoids (MIBOs). At 3.5 weeks, MIBOs replicated Dorsal-Ventral patterning observed in the Ganglionic Eminence (GE). Analysis of matured MIBOs through single-cell RNA sequencing revealed distinct Dorsal GE derived CALB2+ interneurons (INs), Medium Spiny Neurons (MSNs), and MGE derived cell types. Finally, we demonstrate long term culturing capabilities with MIBOs maintaining stable neural activity in cultures grown up to 5.5 months. MIBOs demonstrate a versatile approach for generating spatially patterned brain organoids for embryonic development and disease modeling.

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Section: Characterizing the Functioning Neural Circuits In Mibos Usin...supporting

confidence: 87%

Patterning ganglionic eminences in developing human brain organoids using morphogen gradient inducing device

Pavon,

Diep,

Yang

et al. 2023

Preprint

Self Cite

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“…The gene expression values for these genes from our previous RNA-seq study ( Brocato and Wolstenholme, 2023 ) are shown in Supplementary Figure S4 . Specifically, Kcnh7 , Nrxn1 and Cntn5 have been associated with myelin formation or phenotypes ( Boscia et al, 2021 ; Dauar et al, 2022 ; Sebastian et al, 2022 ), and glutamate signaling has been shown to be important to oligodendrocyte development and survival ( Kougioumtzidou et al, 2017 ; Turan et al, 2021 ). Changes to the regulation of these genes and others involved in synaptic function could impact the progression of oligodendrocyte maturation and play a role in ethanol-induced myelin reduction.…”

Section: Discussionmentioning

confidence: 99%

Adolescent binge ethanol impacts H3K9me3-occupancy at synaptic genes and the regulation of oligodendrocyte development

Brocato,

Easter,

Morgan

et al. 2024

Front. Mol. Neurosci.

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IntroductionBinge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the susceptibility of these changes. Animal models to understand ethanol’s actions on myelin and white matter show that adolescent binge ethanol can alter the developmental trajectory of oligodendrocytes, myelin structure, and myelin fiber density. Oligodendrocyte differentiation is epigenetically regulated by H3K9 trimethylation (H3K9me3). Prior studies have shown that adolescent binge ethanol dysregulates H3K9 methylation and decreases H3K9-related gene expression in the PFC.MethodsHere, we assessed ethanol-induced changes to H3K9me3 occupancy at genomic loci in the developing adolescent PFC. We further assessed ethanol-induced changes at the transcription level with qPCR time course approaches in oligodendrocyte-enriched cells to assess changes in oligodendrocyte progenitor and oligodendrocytes specifically.ResultsAdolescent binge ethanol altered H3K9me3 regulation of synaptic-related genes and genes specific for glutamate and potassium channels in a sex-specific manner. In PFC tissue, we found an early change in gene expression in transcription factors associated with oligodendrocyte differentiation that may lead to the later significant decrease in myelin-related gene expression. This effect appeared stronger in males.ConclusionFurther exploration in oligodendrocyte cell enrichment time course and dose response studies could suggest lasting dysregulation of oligodendrocyte maturation at the transcriptional level. Overall, these studies suggest that binge ethanol may impede oligodendrocyte differentiation required for ongoing myelin development in the PFC by altering H3K9me3 occupancy at synaptic-related genes. We identify potential genes that may be contributing to adolescent binge ethanol-related myelin loss.

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“…Neurexin 1 (NRXN1) deletions are linked to increased risk in schizophrenia. Along with cell-specific transcriptional changes, organoids with NRXN1 deletions displayed decreased synchronized calcium burst activity at 4-5 months of culture compared to control organoids (Sebastian et al, 2023). Network oscillations have also been found to be altered in organoids subject to different pressure shockwaves modeling primary blast injury.…”

Section: Astrocyte Coordination Of Neural Network Activity Within Org...mentioning

confidence: 97%

Asteroid impact: the potential of astrocytes to modulate human neural networks within organoids

Lavekar,

Patel,

Montalvo-Parra

et al. 2023

Front. Neurosci.

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Astrocytes are a vital cellular component of the central nervous system that impact neuronal function in both healthy and pathological states. This includes intercellular signals to neurons and non-neuronal cells during development, maturation, and aging that can modulate neural network formation, plasticity, and maintenance. Recently, human pluripotent stem cell-derived neural aggregate cultures, known as neurospheres or organoids, have emerged as improved experimental platforms for basic and pre-clinical neuroscience compared to traditional approaches. Here, we summarize the potential capability of using organoids to further understand the mechanistic role of astrocytes upon neural networks, including the production of extracellular matrix components and reactive signaling cues. Additionally, we discuss the application of organoid models to investigate the astrocyte-dependent aspects of neuropathological diseases and to test astrocyte-inspired technologies. We examine the shortcomings of organoid-based experimental platforms and plausible improvements made possible by cutting-edge neuroengineering technologies. These advancements are expected to enable the development of improved diagnostic strategies and high-throughput translational applications regarding neuroregeneration.

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Schizophrenia-associatedNRXN1deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids

Cited by 4 publications

References 119 publications

Patterning ganglionic eminences in developing human brain organoids using morphogen gradient inducing device

Patterning ganglionic eminences in developing human brain organoids using morphogen gradient inducing device

Adolescent binge ethanol impacts H3K9me3-occupancy at synaptic genes and the regulation of oligodendrocyte development

Asteroid impact: the potential of astrocytes to modulate human neural networks within organoids

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