Progress in iPSC-Based Modeling of Psychiatric Disorders

Area of Science:

• Neuroscience
• Developmental Biology
• Psychiatry

Background:

• Schizophrenia (SCZ) is a complex psychiatric disorder with high heritability, suggesting a strong genetic influence on brain development.
• Induced pluripotent stem cell (iPSC)-based models offer a powerful tool to study human brain development and neurodevelopmental deviations in SCZ.

Purpose of the Study:

• To investigate the impact of genetic risk in SCZ on early human brain development using iPSC-derived cellular systems.
• To explore how SCZ-related genetic vulnerabilities affect neural progenitor cells (NPCs), neocorticogenesis, and circuit formation in vitro and in vivo.

Main Methods:

• Utilized iPSC technology to generate neural progenitor cells (NPCs) and brain organoids from patients with SCZ.
• Assessed functional impairments in NPCs, neocorticogenesis, hippocampal circuit formation, and glial development in iPSC models.
• Examined oligodendrocyte and astrocyte development in chimeric mice models to understand in vivo cell-cell interactions in SCZ pathogenesis.

Main Results:

• iPSC-derived NPCs and brain organoids from SCZ patients exhibit disrupted neocorticogenesis and impaired hippocampal circuit-like structure formation.
• Defects in glial development, including oligodendrocytes and astrocytes, were observed in both iPSC models and chimeric mice, suggesting altered cell-cell interactions.
• Evidence points to cell-autonomous defects in cortical interneuron (cIN) development contributing to excitatory-inhibitory imbalances in SCZ.

Conclusions:

• Genetic risk factors in SCZ significantly impact critical developmental processes including neocorticogenesis, hippocampal circuit assembly, and the differentiation of specific neuronal and glial subtypes.
• iPSC-based research provides valuable insights into the cellular and circuit-level neuropathology underlying early-onset SCZ, paving the way for future therapeutic strategies.
• Further advancements in iPSC-based investigations are crucial to fully elucidate the complex pathogenesis of psychiatric disorders.