Modelling schizophrenia using human induced pluripotent stem cells
Open accessAbstract
Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.
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2D iPSC models have been important for analysing gene expression, cell morphology, neuronal excitability and synapse formation, and have shed light on mechanisms underlying schizophrenia, bipolar disorder and Rett syndrome.
“2D iPSC models have been important for analysing parameters such as gene expression, cell morphology, neuronal excitability, and synapse formation76,77 and have shed light on mechanisms underlying disorders such as schizophrenia78,79, bipolar disorder78–80, and Rett syndrome81”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [78]
Schizophrenia hiPSC-derived neurons had significantly reduced neuronal connectivity, reduced neurite outgrowth, reduced dendritic PSD95 levels, and altered gene expression profiles.
“Schizophrenia-hiPSC-derived neurons had significantly reduced neuronal connectivity, reduced neurite outgrowth, reduced dendritic levels of PSD95, and altered gene expression profiles.”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Brennand et al., 2011
Defects in neuronal connectivity and gene expression in schizophrenia hiPSC-derived neurons were ameliorated following treatment with the dopamine receptor antagonist loxapine.
“Defects in neuronal connectivity and gene expression were ameliorated following treatment with the dopamine receptor antagonist loxapine.”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Brennand et al., 2011
hiPSC-derived neurons from patients with psychiatric disorders exhibit significant aberrations in neuronal connectivity, synapse maturation, and synaptic function compared with healthy controls.
“As a proof-of-principle, several recent studies have now shown that hiPSC-derived neurons from patients with psychiatric disorders exhibit significant aberrations in neuronal connectivity, synapse maturation, and synaptic function compared with those of healthy controls (Brennand et al., 2011; Cheung et al., 2011; Marchetto et al., 2010; Pasca et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Brennand et al., 2011
Stem cell-based models are beginning to be used for characterizing cellular defects linked to pathological gene variation.
“and stem cell-based models are beginning to be used for characterizing cellular defects linked to pathological gene variation 58-60 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [60]
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- Authors
- Brennand, K. J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., McCarthy, S., Sebat, J., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- Pennsylvania State University (US)
- Cold Spring Harbor Laboratory (US)
- University of California San Diego (US)
- Corresponding author
- Gage, Fred H.
- Venue
- Nature
- Published
- 2011-04-13
- Volume
- 473
- Issue
- 7346
- Pages
- 221-225
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3392969
- OpenAlex
- W2060801754
- Cited by
- 1,375
- References
- 23
- Citations by year
- 2026: 35 · 2025: 35 · 2024: 61 · 2023: 47 · 2022: 68 · 2021: 81 · 2020: 94 · 2019: 90 · 2018: 79 · 2017: 96 · 2016: 122 · 2015: 119 · 2014: 103 · 2013: 139 · 2012: 135
- FWCI
- 57.97
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-10-19)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH083911)
- National Institute of Neurological Disorders and Stroke (P01NS028121, P30NS072031)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- schizophrenia, human induced pluripotent stem cells, iPSC-derived neurons, fibroblast reprogramming, neuronal connectivity, PSD-95, glutamate receptors, cAMP signaling, Wnt signaling, gene expression profiling, loxapine, disease modeling
- MeSH terms
- Disks Large Homolog 4 Protein, Adolescent, Adult, Cell Differentiation, Cells, Cultured, Child, Female, Fibroblasts, Gene Expression Regulation, Humans, Loxapine, Male, Membrane Proteins, Models, Biological, Neurons, Phenotype, Schizophrenia, Antipsychotic Agents, Neurites, Receptors, Glutamate, Gene Expression Profiling, Pluripotent Stem Cells, Intracellular Signaling Peptides and Proteins, Young Adult, Cellular Reprogramming
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