Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells

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.

Mitochondrial Dysfunction in Schizophrenia

“…[ 9 ] However, understanding of developmental pathogenesis had been limited due to the lack of such tissues. iPSC technology allows the generation of such developmental tissues [ 93 ] that possess the same genetic makeup as the patient and are not confounded by age, antipsychotic treatment, or life history, allowing us to explore early developmental molecular and cellular endophenotypes from patients with SCZ, as long as disease‐relevant tissues can be reliably and homogenously derived.…”

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

“…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.…”

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

“…Clinically, this is consistent with the general consensus that SCZ is strictly neuropsychiatric as opposed to degenerative. In this same vein, axonogenesis (p_microglia<2.91e-5, p_oligodencrocytes<4.56e-12, p_excitatory<5.27e-17, p_inhibitory<7.91e-16) [68], regulation of cell morphogenesis (p_microglia<1.01e-8, p_oligodencrocytes<9.11e-10, p_excitatory<1.56e-8, p_inhibitory<2.65e-9) [69], neuronal cell synapses (p_oligodencrocytes<7.26e-11, p_excitatory<2.28e-25, p_inhibitory<2.17e-26) [49] were all enriched. Multiple axon guidance pathways associated with general axon growth in axonogenesis have been heavily implicated in the broad mechanism of SCZ pathology; elucidating this mechanism has remained difficult in part due to the polygenic nature of the disease.…”

“…Broadly, it is thought that missteps in guidance cues can lead to eventual presentation and disease onset, but the underlying pathway remains unclear [68]. On the front of cell morphogenesis, early life neurodevelopmental genetic markers may suggest causal links with alterations in hippocampal cell differentiation points leading to cascades of downstream effects [69]. This has primarily been studied and modeled within the scope of iPSC-based analyses, which make correlations and connections to the clinical presentation more difficult due to the additional abstraction from standard pathology-based analysis.…”