Progress in iPSC-Based Modeling of Psychiatric Disorders

Abstract

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.

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

“…Synaptic connections formed within this microfluidic system as evidenced by a rabies virus tracing assay. Moreover, multi-electrode array (MEA) recordings and whole-cell patch clamp techniques showed that the SCZ hCA3 neurons were impaired in both spontaneous and evoked electrophysiological activity (see also [63]).…”

“…Beyond in vitro studies, transplanting of human brain organoids into mouse brains was recently performed to establish an in vivo model of human brain neuronal connectivity [111]. Human brain organoids underwent vascularization and integration with microglia, extended long-range axons, and exhibited synchronized neural activity and functional connectivity within the mouse brain (see also [63]). In a nutshell, human brain organoid in vitro and in vivo systems open up multiple opportunities to investigate causal mechanisms and genes on cellular phenotypes lying at the heart of psychiatric disorders.…”

“…Independent transgenic mice and postmortem brain analysis further supported an early and cell-autonomous defect in cINs. Although credible SNPs in PCDHAs could not be identified owing a lack of statistical power, this study highlights the potential of phenotype-driven iPSC-based disease modeling for dissecting causal mechanisms in SCZ (see also [63]).…”

What Does Immunology Have to Do With Normal Brain Development and the Pathophysiology Underlying Tourette Syndrome and Related Neuropsychiatric Disorders?

“…Finally, proteomics using induced pluripotent stem cells (iPSC)-derived neurons and microglia from individuals with TS and related disorders will continue to push the field toward better understanding of disease pathophysiology which hopefully will contribute to the future development of therapeutics against specific targets (204,205).…”

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

“…The use of iPSC-based models for the latter disease type is more problematic with respect to monogenic diseases, since the phenotype is often the result of multiple small-effect genetic variants in combination with environmental factors. However, this approach was used to model many different complex diseases including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and cardiac arrhythmias [ 132 , 133 , 134 , 135 ]. Without knowing the detailed underlying genetics, differentiated patient-specific iPSCs could provide disease-relevant cells that carry all the genetic elements implicated in the development of the disease and can be useful to analyze the common mechanisms of disease development.…”