Induced Pluripotent Stem Cell Models in Neuropsychiatric Disorders

Induced pluripotent stem cells (iPSCs) have revolutionised the study of neuropsychiatric disorders by providing patient-specific platforms to model disease-relevant cell types in vitro. Through reprogramming of adult somatic cells into a pluripotent state, researchers can generate neural progenitor cells, defined neuronal subtypes and three-dimensional brain organoids that retain the donor’s genetic background. These models have illuminated disease mechanisms at multiple levels, from early developmental trajectories to synaptic connectivity and network synchronisation. iPSC-derived neurons reveal cell-type-specific vulnerabilities, such as altered dendritic spine density in cortical pyramidal cells and excitatory/inhibitory imbalance in GABAergic networks. Organoid systems recapitulate aspects of cortical lamination and allow interrogation of developmental timing in conditions like schizophrenia and bipolar disorder. Advances in single-cell transcriptomics, genome editing and high-throughput electrophysiology now permit comprehensive phenotyping and drug screening in vitro. Such approaches offer unprecedented insight into the molecular and cellular underpinnings of mental illness and hold promise for personalised therapeutic strategies and mechanistic biomarkers.

Research from Nature Portfolio

Recent studies have used human forebrain organoids carrying heterozygous deletions in synaptic adhesion genes to dissect cell-type and developmental-timing vulnerabilities in schizophrenia. Single-cell transcriptomic profiling across organoid maturation revealed distinct perturbations in neural progenitors and excitatory versus inhibitory neuronal lineages, accompanied by long-lasting synaptic network deficits measured by calcium imaging. Another foundational work has demonstrated that rigorous control of differentiation variability in large hiPSC cohorts can enhance the detection of disease-associated transcriptional signatures. By aligning iPSC-derived neural progenitor and neuronal profiles with post-mortem datasets, this study established a roadmap for optimising cohort size and clone selection to maximise signal in complex genetic disorders.

Induced Pluripotent Stem Cell Models in Neuropsychiatric Disorders publication trend

The graph below shows the total number of articles in induced pluripotent stem cell models in neuropsychiatric disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Induced pluripotent stem cell (iPSC): An adult somatic cell reprogrammed to a pluripotent state capable of differentiating into any cell type.

Brain organoid: A three-dimensional assembly of stem cell-derived neural cells that mimics aspects of early brain development and tissue architecture.

Neural progenitor cell (NPC): A multipotent precursor that gives rise to various neuronal and glial lineages during development.

Excitatory/inhibitory balance: The homeostatic equilibrium between stimulating and suppressing synaptic inputs that underlies proper neural network function.

References

1. Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids. Nature Communications (2023).
2. Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nature Communications (2017).
3. Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia. Genome Medicine (2023).
4. Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission. Molecular Psychiatry (2024).
5. Neurobiological Perturbations in Bipolar Disorder Compared With Schizophrenia: Evidence From Cell Cultures and Brain Organoids. Biological Psychiatry (2025).
6. Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders. F1000Research (2018).
7. Aberrant neuronal connectivity and network activity of neurons derived from patients with idiopathic schizophrenia. Neurobiology of Disease (2024).
8. Cerebral organoids reveal early cortical maldevelopment in schizophrenia—computational anatomy and genomics, role of FGFR1. Translational Psychiatry (2017).