Table 1.
Selection of Findings From iPSC-Derived Models for Psychiatric Disorders
| Disorder | Model | Results | Reference |
|---|---|---|---|
| Neurodegenerative disorders | |||
| iPSC-derived neurons of different origins | Insights into mechanisms of release, uptake, and toxicity of disease-associated proteins, including α-Synuclein, tau, amyloid-β, huntingtin, and TDP-43 | (de Rus Jacquet et al., 2021) (review) | |
| Substance use disorders | |||
| Alcohol | iPSC-derived neurons of different origins | Altered NMDA-receptor activity and involvement of different subunits of the GABA-A receptor in the pathomechanisms of alcohol use disorder | (McNeill et al., 2020) (review) |
| Astrocytes and forebrain neurons generated from fibroblast-derived iPSCs | Downregulation of TSPAN5 and similar effects of ethanol and acamprosate on serotonin concentrations in culture | (Ho et al., 2020) | |
| Forebrain neurons generated from fibroblast-derived iPSCs | Changes of gene expression associated with cholesterol homeostasis through alcohol | (Jensen et al., 2019) | |
| Cannabis | Cortical neurons generated from keratinocyte-derived iPSCs | iPSC-derived cortical neurons predominantly express the cannabinoid type 1, which responds to exogeneous cannabinoids; THC affects neurite outgrowth | (Shum et al., 2020) |
| Forebrain neurons generated from fibroblast-derived iPSCs | Dampened cellular and molecular phenotype through THC; changes in THC-associated genes also implicated in psychiatric disorders | (Guennewig et al., 2018) | |
| Opioids | GABA-ergic neurons generated from primary lymphocyte-derived iPSCs (in combination with CRISPR/Cas9 | SNP of µ-opioid receptor (N40D) affects spontaneous inhibitory currents | (Halikere et al., 2020) |
| Schizophrenia | |||
| iPSC-derived neurons of different origins | Alterations in synaptic transmission, energy metabolism and disturbed neuronal development | (Sauerzopf et al., 2017) (review) | |
| Cortical neurons generated from fibroblast-derived iPSCs in combination with CRISPR/Cas9 | Mutation of DISC1 affects interaction with ATF4 on structural and molecular levels | (Wang et al., 2021) | |
| iPSCs derived from PBMCs | Feasibility of generating iPSCs from PBMCs with an exonic deletion of ASTN2, with potential to differentiate into 3 germ layers | (Arioka et al., 2018) | |
| Cortical neurons generated from PBMC-derived iPSCs | Reelin gene mutation (deletion) associated with increased neuronal cell death | (Arioka et al., 2020) | |
| iPSCs derived from PBMCs | Feasibility of generating iPSCs from PBMCs with de novo mutations in KHSRP, LRRC7, and KIR2DL1, with potential to differentiate into 3 germ layers | (Hathy et al., 2021) | |
| Forebrain neurons and oligodendrocyte progenitor cells generated from fibroblast-derived iPSCs | Abnormal cellular morphology and myelination potential in iPSC derived OPCs with 2 missense mutations in the CSPG4 gene of patients with schizophrenia | (de Vrij et al., 2019) | |
| Cortical neurons generated from fibroblast-derived iPSCs (and induced microglia-like cells derived from PBMCs) | Increased synapse elimination and synaptic pruning through microglia in cortical neurons from patients with schizophrenia, improved through minocycline | (Sellgren et al., 2019) | |
| Glutamatergic neurons generated from fibroblast-derived iPSCs | Persistent changes in iPSC-derived interneurons through microglia | (Park et al., 2020) | |
| Glutamatergic neurons generated from fibroblast-derived iPSCs | Aberrant arborization and synaptic density in neurons from patients with schizophrenia, rescued with inhibitor of protein kinase C inhibitor | (Shao et al., 2019) | |
| NPCs generated from fibroblast-derived iPSCs | Method to perform drug screening using transcriptomic profile changes when applying 135 different drugs | (Readhead et al., 2018) | |
| Affective disorders | |||
| Bipolar disorder | iPSC-derived neurons of different origins | Dysregulations of neurodevelopmental and electrophysiological aspects | (Hoffmann et al., 2018) (review) |
| Forebrain neurons generated from fibroblast-derived iPSCs | Effect of lithium on calcium signaling, potentially useful for prediction of treatment response | (Chen et al., 2014) | |
| Major depressive disorder | Hindbrain serotonergic neurons generated from fibroblast-derived iPSCs | Association of both altered growth and morphology of serotonergic neurons and SSRI-resistance in MDD patients | (Vadodaria et al., 2019a) |
| Forebrain neurons (mixture of glutamatergic and GABAergic) generated from fibroblast-derived iPSCs | Serotonin-induced postsynaptic neuronal hyperactivity in non-remitters | (Vadodaria et al., 2019b) | |
| Neurodevelopmental disorders | |||
| ASDs | iPSC-derived neurons of different origins | Modelling of neurodevelopment and drug discovery using iPSC-derived neurons in neurodevelopmental disorders | (Wen, 2017) (review) |
| iPSC-derived neurons of different origins | Approaches to model ASD using iPSC-derived neurons (and organoids) | (Ilieva et al., 2018) (review) | |
| iPSC-derived neurons of different origins | Implication of calcium signaling, electrophysiology, cell proliferation, and synaptic density as potential disease phenotypes | (Pintacuda et al., 2021) (review) | |
| Motorneurons generated from iPSC | Impairment of neuromuscular junction maturation through SHANK3 | (Lutz et al., 2020) | |
| NPCs and glutamatergic and GABA-ergic neurons generated from SHED | Dysregulations of specific modules connected to protein synthesis and synapse/transmission in NPCs and neurons | (Griesi-Oliveira et al., 2020) | |
| ADHD | iPSCs generated from urine epithelial cells | Feasibility of generating iPSCs from urine epithelial cells, that can be used as a model for ADHD in the future | (Sochacki et al., 2016) |
| iPSCs generated from fibroblasts | Feasibility of generating iPSCs with a SLC2A3 mutation from fibroblasts, that could be differentiated into all 3 germ layers, as a model for ADHD in the future | (Jansch et al., 2018) | |
| iPSCs generated from PBMCs | Feasibility of generating iPSCs from PBMCs, that can be used as a model for ADHD in the future | (Tong et al., 2019) | |
| iPSCs generated from PBMCs and keratinocytes (of children and adolescents aged 6–18) | Feasibility of generating iPSCs from PBMCs and keratinocytes, that can be used as a model for ADHD in the future | (Grossmann et al., 2021) | |
| NPC generated from keratinocyte-derived iPSCs | Generation of NPCs from keratinocyte-derived iPSCs to study molecular and cellular processes in ADHD | (Re et al., 2018) | |
| Midbrain dopaminergic neurons generated from fibroblast-derived iPSCs (with a CNV in the PARK2 locus) | Alterations in mitochondrial dynamics through PARK2 CNV, which might impact neuronal development | (Palladino et al., 2020) |
Abbreviations: ADHD, attention deficit and hyperactivity disorder; ASD, autism spectrum disorder; ASTN2, Astrotactin 2; ATF4, Activating transcription factor 4; CNV, copy number variation; CRISPR/Cas9, Clustered Regularly Interspaced Short Palindromic Repeats/ CRISPR associated protein 9; CSPG4, Chondroitin Sulfate Proteoglycan 4; DISC1, disrupted in schizophrenia 1; iPSC, induced pluripotent stem cells; NPC, neuronal progenitor cells; GABA, gamma-aminobutyric acid; KHSRP, KH-Type Splicing Regulatory Protein; KIR2DL1, killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1; LRRC7, Leucine Rich Repeat Containing 7; MDD, major depressive disorder; NMDA, N-methyl-D-aspartate; OPC, oligodendrocyte progenitor cells; PBMC, peripheral blood mononuclear cells; PARK2, parkin; SHANK3, SH3 And Multiple Ankyrin Repeat Domains 3; SHED, stem cells from human exfoliated deciduous teeth; SLC2A3, Solute Carrier Family 2 Member 3; SNP, single nucleotide polymorphism; SSRI, selective serotonin reuptake inhibitor; TDP43, TAR DNA-binding 43 protein; THC, Δ9-tetrahydrocannabinol; TSPAN5, Tetraspanin 5.