Abstract
Schizophrenia (SCZ) is a devastating mental disorder that is characterized by distortions in thinking, perception, emotion, language, sense of self, and behavior. Epidemiological evidence suggests that subtle perturbations in early neurodevelopment increase later susceptibility for disease, which typically manifests in adolescence to early adulthood. Early perturbations are thought to be significantly mediated through incompletely understood genetic risk factors. The advent of induced pluripotent stem cell (iPSC) technology allows for the in vitro analysis of disease-relevant neuronal cell types from the early stages of human brain development. Since iPSCs capture each donor’s genotype, comparison between neuronal cells derived from healthy and diseased individuals can provide important insights into the molecular and cellular basis of SCZ. In this review, we discuss results from an increasing number of iPSC-based SCZ/control studies that highlight alterations in neuronal differentiation, maturation, and neurotransmission in addition to perturbed mitochondrial function and micro-RNA expression. In light of this remarkable progress, we consider also ongoing challenges from the field of iPSC-based disease modeling that call for further improvements on the generation and design of patient-specific iPSC studies to ultimately progress from basic studies on SCZ to tailored treatments.
Highlights
Schizophrenia (SCZ) has a lifetime prevalence of ≈1% worldwide [1] and confers substantial mortality and morbidity
Since most of these studies refer to adult case/control cohorts, future neuroimaging needs to be placed in the context of normative developmental and atrophic changes in neural structures relevant to SCZ to inform on the role of early neurodevelopment
Reduced activity-dependent transcription, coexpression modules are enriched for Genome-wide association studies (GWAS) risk variants
Summary
Schizophrenia (SCZ) has a lifetime prevalence of ≈1% worldwide [1] and confers substantial mortality and morbidity. Neural cells that are generated from patient-specific induced pluripotent stem cell (iPSCs) capture a donor’s genotype, including disease related genetic risk factors, known and unknown. Analysis of their effects on cellular and molecular endophenotypes during early neurodevelopmental stages in vitro is postulated to cast new light on the potential neurodevelopmental origin of SCZ. To support this hypothesis, we will consider current evidence for an early neurodevelopmental component of idiopathic SCZ by summarizing clinical course, epidemiological, neuroimaging, and histological data, and recent insight into SCZ’s complex genetic architecture. Additional searches included scrutiny of similar articles suggested by PubMed, of references from the identified publications, and of citatory publications identified by Google Scholar®
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