Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells

Hoffmann, Anke; Ziller, Michael J.; Spengler, Dietmar

doi:10.3390/ijms19123829

Cited by 26 publications

(25 citation statements)

References 151 publications

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“…Following pioneering work by Brennand et al [19], the number of iPSC-based case/control studies on SCZ and BD has increased steadily over the last years (reviewed in [20,21,22]). These studies measured in neuronal cells from patients with SCZ (i) reduced neuronal connectivity, (ii) attenuated activity-dependent transcription, (iii) impaired mitochondrial function and increased oxidative stress, (iv) delayed NPC differentiation and neuronal maturation, and (v) altered miRNA expression.…”

Section: Introductionmentioning

confidence: 99%

Progress in iPSC-Based Modeling of Psychiatric Disorders

Hoffmann

Ziller

Spengler

2019

IJMS

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Progress in iPSC-based cellular systems provides new insights into human brain development and early neurodevelopmental deviations in psychiatric disorders. Among these, studies on schizophrenia (SCZ) take a prominent role owing to its high heritability and multifarious evidence that it evolves from a genetically induced vulnerability in brain development. Recent iPSC studies on patients with SCZ indicate that functional impairments of neural progenitor cells (NPCs) in monolayer culture extend to brain organoids by disrupting neocorticogenesis in an in vitro model. In addition, the formation of hippocampal circuit-like structures in vitro is impaired in patients with SCZ as is the case for glia development. Intriguingly, chimeric-mice experiments show altered oligodendrocyte and astrocyte development in vivo that highlights the importance of cell–cell interactions in the pathogenesis of early-onset SCZ. Likewise, cortical imbalances in excitatory–inhibitory signaling may result from a cell-autonomous defect in cortical interneuron (cIN) development. Overall, these findings indicate that genetic risk in SCZ impacts neocorticogenesis, hippocampal circuit formation, and the development of distinct glial and neuronal subtypes. In light of this remarkable progress, we discuss current limitations and further steps necessary to harvest the full potential of iPSC-based investigations on psychiatric disorders.

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Section: Introductionmentioning

confidence: 99%

Progress in iPSC-Based Modeling of Psychiatric Disorders

Hoffmann

Ziller

Spengler

2019

IJMS

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“…Several recent studies profiled the phenotype of iPSC-derived neurons from donors with SCZ associated with CNVs, whose deficits were most likely produced by the genetic mutation. Among the neurons obtained from iPSC most were glutamatergic, few were GABAergic and none were DA neurons (Hoffmann et al, 2018). Delayed development was observed in iPSC-derived glutamatergic neurons from donors with 22q11 microdeletion (Pedrosa et al, 2011).…”

Section: Ipsc-derived Neurons In Genetically Profiled Subjects With Smentioning

confidence: 94%

Negative Symptoms of Schizophrenia and Dopaminergic Transmission: Translational Models and Perspectives Opened by iPSC Techniques

et al. 2020

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Negative symptoms (NS) represent a heterogeneous dimension of schizophrenia (SCZ), associated with a poor functional outcome. A dysregulated dopamine (DA) system, including a reduced D1 receptor activation in the prefrontal cortex, DA hypoactivity in the caudate and alterations in D3 receptor activity, seems to contribute to the pathogenesis of NS. However, failure to take into account the NS heterogeneity has slowed down progress in research on their neurobiological correlates and discoveries of new effective treatments. A better neurobiological characterization of NS is needed, and this requires objective quantification of their features that can be applied in translational models, such as animal models and human inducible pluripotent stem cells (iPSC). In this review we summarize the evidence for dopaminergic alterations relevant to NS in translational animal models focusing on dysfunctional motivation, a core aspect of NS. Among others, experiments on mutant rodents with an overexpression of DA D2 or D3 receptors and the dopamine deficient mice are discussed. In the second part we summarize the findings from recent studies using iPSC to model the pathogenesis of SCZ. By retaining the genetic background of risk genetic variants, iPSC offer the possibility to study the effect of de novo mutations or inherited polymorphisms from subgroups of patients and their response to drugs, adding an important tool for personalized psychiatry. Given the key role of DA in NS, we focus on findings of iPSC-derived DA neurons. Since implementation of iPSC-derived neurons to study the neurobiology of SCZ is a relatively recent acquisition, the available data are limited. We highlight some methodological aspects of relevance in the interpretation of in vitro testing results, including limitations and strengths, offering a critical viewpoint for the implementation of future pharmacological studies aimed to the discovery and characterization of novel treatments for NS.

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“…This shortcoming raises the question of what cellular phenotypes are needed to enhance identification of causal mechanisms and genes in psychiatric disorders. Previous studies on patient-specific disease modeling were directed towards gene expression profiling, imaging, electrophysiology, proteomic approaches, and functional readouts such as proliferation, migration, and maturation (for recent reviews see [103][104][105]. Qualitative and quantitative improvements on these readouts are likely to improve further reproducibility and statistical power from case/control studies.…”

Section: Outlook and Discussionmentioning

confidence: 99%

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders

Hoffmann

Ziller

Spengler

2020

Cells

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Genome-wide association studies (GWAS) have identified an increasing number of genetic variants that significantly associate with psychiatric disorders. Despite this wealth of information, our knowledge of which variants causally contribute to disease, how they interact, and even more so of the functions they regulate, is still poor. The availability of embryonic stem cells (ESCs) and the advent of patient-specific induced pluripotent stem cells (iPSCs) has opened new opportunities to investigate genetic risk variants in living disease-relevant cells. Here, we analyze how this progress has contributed to the analysis of causal relationships between genetic risk variants and neuronal phenotypes, especially in schizophrenia (SCZ) and bipolar disorder (BD). Studies on rare, highly penetrant risk variants have originally led the field, until more recently when the development of (epi-) genetic editing techniques spurred studies on cause-effect relationships between common low risk variants and their associated neuronal phenotypes. This reorientation not only offers new insights, but also raises issues on interpretability. Concluding, we consider potential caveats and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders.

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Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells

Cited by 26 publications

References 151 publications

Progress in iPSC-Based Modeling of Psychiatric Disorders

Progress in iPSC-Based Modeling of Psychiatric Disorders

Negative Symptoms of Schizophrenia and Dopaminergic Transmission: Translational Models and Perspectives Opened by iPSC Techniques

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders

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