Identification of neuron-glia signaling feedback in human schizophrenia using patient-derived, mix-and-match forebrain assembloids
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Abstract
Although abnormal activities across multiple cell types are believed to contribute to the development of various neurodevelopmental disorders, current brain organoid technologies fall short in accurately modeling the dynamic cellular interactions in the human brain. Recently, we developed a cellular reconstitution technology to create human forebrain assembloids with enhanced cellular diversity, representing dynamic interactions between neurons and glial cells. Here, we created patient-derived, mix-and-match forebrain assembloids, in which neurons, astrocytes, and microglia from both healthy individuals and schizophrenia patients were reconstituted in a combinatorial manner, and identified aberrant cellular interactions between neurons and glial cells in human schizophrenia. At the early stage, schizophrenia forebrain assembloids showed premature neurogenesis induced by the abnormal proliferation and differentiation of neural progenitor cells. Integrated modular analysis of gene expression in post-mortem schizophrenia brain tissue and brain assembloids found increased expression of tumor protein p53 (TP53) and nuclear factor of activated T-cells 4 (NFATC4), which functioned as master transcriptional regulators to epigenetically reprogram the transcriptome involved in the cellular dynamics of neuronal progenitor cells, leading to premature neurogenesis. At the later stage, we observed weakened structures of laminar organization of the cortical layers in forebrain assembloids and identified the neuron-dependent transcriptional plasticity of glial cells and their altered signaling feedback with neurons, in which neuronal urocortin (UCN) and protein tyrosine phosphatase receptor type F (PTPRF) elicited the expression of Wnt family member 11 (WNT11) and thrombospondin 4 (THBS4) in astrocytes and microglia, respectively. These aberrant signaling axes altered the neuronal transcriptome associated with neuronal response to various stimuli and synthetic processes of biomolecules, resulting in reduced synapse connectivity. Thus, we elucidated developmental stage-specific, multifactorial mechanisms by which dynamic cellular interplay among neural progenitor cells, neurons, and glial cells contribute to the development of the human schizophrenia brain. Our study further demonstrated the potential and applicability of patient-derived forebrain assembloid technology to advance our understanding of the pathogenesis of various neurodevelopmental disorders.
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In this study, we developed SCZ-specific brain assembloids that, we believe, may overcome many limitations in studying the pathogenesis of human SCZ, such as the lack of systems representing different stages of developing human brains with cellular complexity.
I think this is one important crux of the study, and could lead to resources useful for the field.
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all four combinatorial forebrain assembloids containing neurons derived from patients with SCZ (SHH, SHS, SSH and SSS) exhibited functional abnormalities, such as decrease of synaptic density, neural excitability, and synapse transmission (Fig. 3b-d and Supplementary Fig. 6a,b),
Could an alternative explanation here be what I mention below, that astrocytes and microglia are doped into the neuronal system later in "development" and thus are not integrated physiologically into the system? Could you test this by looking at the physiology of glial themselves under different assembloid conditions, such as microglial movement (as you did in the previous preprint?) and astrocyte-specific calcium signaling? A related query would be making sure that what you're counting as calcium spikes are truly only coming from neuronal activity. Fluo-4 is …
all four combinatorial forebrain assembloids containing neurons derived from patients with SCZ (SHH, SHS, SSH and SSS) exhibited functional abnormalities, such as decrease of synaptic density, neural excitability, and synapse transmission (Fig. 3b-d and Supplementary Fig. 6a,b),
Could an alternative explanation here be what I mention below, that astrocytes and microglia are doped into the neuronal system later in "development" and thus are not integrated physiologically into the system? Could you test this by looking at the physiology of glial themselves under different assembloid conditions, such as microglial movement (as you did in the previous preprint?) and astrocyte-specific calcium signaling? A related query would be making sure that what you're counting as calcium spikes are truly only coming from neuronal activity. Fluo-4 is known to preferentially load into cortical astrocytes in acute slices, so some of these calcium bursts may not be strictly neuronal.
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This plasticity of glial cells is likely to be dictated by SCZ neurons, which accounts for the functional abnormalities and other phenotypic changes found in mix-and-match SCZ forebrain assembloids reconstituted with glial cells derived from healthy individuals.
How much do you think this neuron-driven plasticity is derived from the protocol of adding in glia late in the assembloid process? Could the glial cells be integrating in non-physiological ways because of this? Would you predict that different timing of additional of glia change these results?
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