Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia

Koskuvi, Marja; Lehtonen, Šárka; Trontti, Kalevi; Keuters, Meike Hedwig; Wu, Ying‐Chieh; Koivisto, Hennariikka; Ludwig, Anastasia; Plotnikova, L. M.; Virtanen, Pekka; Räsänen, Noora; Kaipainen, Satu; Hyötyläinen, Ida; Dhungana, Hiramani; Giniatullina, Raisa; Ojansuu, Ilkka; Vaurio, Olli; Cannon, Tyrone D.; Lönnqvist, Jouko; Therman, Sebastian; Suvisaari, Jaana; Kaprio, Jaakko; Lähteenvuo, Markku; Tohka, Jussi; Giniatullin, Rashid; Rivera, Claudio; Hovatta, Iiris; Tanila, Heikki; Tiihonen, Jari; Koistinaho, Jari

doi:10.1002/glia.24131

Cited by 23 publications

(21 citation statements)

References 39 publications

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“…Downregulation of extracellular matrix constitution genes were detected from both twins compared to healthy individuals. Alterations in hepatic fibrosis and GP6 signaling pathways in microglia from patients with SCZ are shared with our previous studies in hiPSCcortical neurons and hiPSC-astrocytes of the same individuals (39,40) indicating universal dysregulation of these pathways. The hepatic fibrosis pathways consists of mostly different collagen which are not liver-specific despite the name of the pathway.…”

Section: Discussionsupporting

confidence: 84%

Genetic contribution to microglial activation in schizophrenia

Koistinaho

Koskuvi²,

Pörsti³

et al. 2022

Preprint

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Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Hyperactivation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes, such as AIF1, HLA-DRA and IL1β compared to healthy individuals. Microglia from affected twins had also reduced response to IL1β treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent GO terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of MHC class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have genetic aberrations related to inflammation response and extracellular matrix without contributing to microglia hyperactivation.

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Section: Discussionsupporting

confidence: 84%

Genetic contribution to microglial activation in schizophrenia

Koistinaho

Koskuvi²,

Pörsti³

et al. 2022

Preprint

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“…Given the polygenic nature of SCZ and the significant overlap of the SCZ PRS between cases and controls in the general population [73], the strategy to scale back the influence of genetic variation is required for iPS cell-based modeling of SCZ, especially in the sporadic cases. Analysis of twins discordant for the disorder [74][75][76][77] and modeling the disorder with a relatively large-scale iPS cell cohort are promising strategies [78]. These strategies may, however, not be easily applicable in the majority of studies, because of the rarity of twins cases and an extremely large number of individuals theoretically required that was estimated to be necessary [71].…”

Section: Discussionmentioning

confidence: 99%

Ventral forebrain organoids derived from individuals with schizophrenia recapitulate perturbed striatal gene expression dynamics of the donor’s brains

Sawada

Barbosa

Araújo

et al. 2022

Preprint

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Schizophrenia (SCZ) is a brain disorder originating during neurodevelopment with complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, its cellular and molecular underpinnings remain unclear. Here, to explore neurodevelopmental alterations in the striatum associated with SCZ, we established a method for the differentiation of iPS cells into ventral forebrain organoids. Given substantial genetic heterogeneity among individuals, which can obscure disease-associated phenotypes, we generated organoids from postmortem dural fibroblast-derived iPS cells of 3 patients and 4 healthy control individuals with nonoverlapping polygenic risk score (PRS) for SCZ and whose genotype and postmortem caudate transcriptomic data were profiled in the Brainseq neurogenomics consortium. Single cell RNA sequencing (scRNA-seq) analyses of the organoids revealed differences in developmental trajectory between SCZ cases and controls in which inhibitory neurons from patients exhibited accelerated maturation. Furthermore, we found a significant overlap of genes upregulated in the inhibitory neurons in SCZ organoids with upregulated genes in postmortem caudate tissues from patients with SCZ compared with control individuals, including the donors of our iPS cell cohort. Our findings suggest that striatal neurons in the patients with SCZ carry abnormalities that originated during early brain development and a ventral forebrain striatal organoid model can recapitulate those neurodevelopmental phenotypes in a dish.

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“…The transplantation protocol was adapted from [ 14 ]. The 6.5–7.5-months-old astrospheres were dissociated with Accutase and resuspended at the concentration of 100,000 cells/µL in phosphate-buffered saline (PBS) prior to transplantation.…”

Section: Methodsmentioning

confidence: 99%

Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice

Jäntti

Oksanen

Kettunen

et al. 2022

Cells

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The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected PSEN1 ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months. While we did not find significant behavioral changes in younger mice, spatial learning and memory were paradoxically improved in 16-month-old PSEN1 ΔE9 glia-transplanted male mice as compared to age-matched isogenic control-transplanted animals. Memory improvement was associated with lower levels of soluble, but not insoluble, human Aβ42 in the mouse brain. We also found a decreased engraftment of PSEN1 ΔE9 mutant cells in the cingulate cortex and significant transcriptional changes in both human and mouse genes in the hippocampus, including the extracellular matrix-related genes. Overall, the presence of PSEN1 ΔE9 mutant glia exerted a more beneficial effect on aged mouse brain than the isogenic control human cells likely as a combination of several factors.

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Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia

Cited by 23 publications

References 39 publications

Genetic contribution to microglial activation in schizophrenia

Genetic contribution to microglial activation in schizophrenia

Ventral forebrain organoids derived from individuals with schizophrenia recapitulate perturbed striatal gene expression dynamics of the donor’s brains

Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice

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