TABLE 2.

Selected reports utilizing iPSC models and organoid technologies for the characterization of schizophrenia.

Sample origin		In vitro model	Observation(s)	Implication(s)	Sampling time frame	Subtype selectivity	References
fSZ/sSZ	Fibroblasts	iPSC, differentiated to neural progenitor cells	Abnormal gene and protein levels related to cytoskeletal remodeling and increased oxidative stress	SZ hiPSC NPCs may serve as a proxy for the developmental pathways potentially contributing to SZ pathogenesis	Late-stage	None	Brennand et al., 2015
	Fibroblasts	iPSC, differentiated to CA3 neurons and DG neurons	Reduction of activity in DG-CA3 co-culture and deficits in spontaneous and evoked activity in CA3 neurons	iPSC-derived CA3 neurons and DG neurons may recapitulate SZ hippocampal activity	Late-stage	None	Sarkar et al., 2018
	Fibroblasts	iPSC, differentiated to neural progenitor cells, glutamatergic neurons	Reduced number of neurite and protein level of PSD95	Report decreased neuronal connectivity, synaptic protein level and glutamate receptor expression in SZ iPSC neurons	Late-stage	None	Brennand et al., 2011
	Fibroblasts	iPSC, differentiated to dentate gyrus granule neurons	Reduced hippocampal neurogenesis and attenuated spontaneous neurotransmitter release	iPSC-derived DG granule neurons recapitulate SZ hippocampal neurogenesis features including lowered level of NEUROD1, PROX1 and TBR1	Late-stage	None	Yu et al., 2014
	Fibroblasts	iPSC, differentiated to forebrain mixed neurons	Increase of gene expression of WNT signaling genes and β-catenin protein levels	Abnormal expression of WNT signaling proteins may underlie SZ	Late-stage	None	Topol et al., 2015
	Fibroblasts	iPSC-derived cerebral organoids	Altered distribution of cortical neurons in correlation with abnormal expression of nuclear FGFR1 in neuronal committed cells	Altered FGFR1 signaling is linked to cortical malformation in SZ patient-derived cerebral organoid models	Late-stage	None	Stachowiak et al., 2017
	Fibroblasts	iPSC-derived cerebral organoids	Increased production of malformative TNF and increased developmental vulnerability to TNF	Development of brain pathology in SZ is exacerbated by abnormal TNF expression	Late-stage	None	Benson et al., 2020
fSZ	Fibroblasts	iPSC, differentiated to neural progenitor cells	Reduced protein level of CYFIP1 and WAVE	15q11.2 microdeletion affects neural developmental processes by altering CYFIP1 signaling and WAVE complex signaling	Childhood-onset SZ	15q11.2 deletion	Yoon et al., 2014
	Fibroblasts	iPSC, differentiated to neurons, neural progenitor cells and oligodendrocyte precursor cells	Decreased expression of exon14-15 of CNTNAP2 and reduced neural migration	Present that both exon-and allele-specific expression of CNTNAP2 may be critical for the predisposition of SZ	Late-stage	Large heterozygous CNTNAP2 deletion	Lee et al., 2015
	Hair follicle keratinocytes	iPSC, differentiated to dopaminergic neurons and glutamatergic neurons	Morphological abnormalities of dopaminergic neurons and mitochondrial dysfunction in keratinocytes	Unravel impaired ability to differentiate into dopaminergic neurons and mitochondrial dysfunction including abnormal mitochondrial membrane potential, trafficking and turnover in SZ	Late-stage	Paranoid SZ	Robicsek et al., 2013
	Fibroblasts	iPSC, differentiated to neural progenitor cells	Downregulation of miR-9 in correlation with reduced migration in neural progenitor cells	miR-9 as a risk factor for SZ	Late-stage and childhood-onset SZ	None	Topol et al., 2016
sSZ	Fibroblasts	iPSC, differentiated to glutamatergic and GABAergic neurons	Reduced expression of almost all genes in the 22q11.2 region	Identified potential druggable targets in neuropsychiatric diseases associated with 22q11.2 del	Late-stage	22q11.2 deletion	Lin et al., 2016
	Fibroblasts	iPSC, differentiated to neural progenitor cells and neurospheres	Reduced expression level of miRNAs belonging to miR-17/92 cluster and miR-106a/b and upregulated p38α	Potential novel p38α-targeting therapeutics for SZ	Late-stage	22q11.2 deletion	Toyoshima et al., 2016
	Fibroblasts	iPSC, differentiated to mixed neurons	Dysregulated expression of miRNAs	Suggest that iPSCs derived from patient with 22q11.2 del SZ may be utilized to study the disease	Late-stage and childhood-onset SZ	22q11.2 deletion	Zhao et al., 2015
	Fibroblasts	iPSC, differentiation to forebrain mixed neurons and MAP2AB + neurons	Reduced wild-type DISC1 protein level and synaptic vesicle release	Mutant DISC1 depletes wild-type DISC1 protein and causes synaptic abnormalities including defects in glutamatergic synaptic transmission and synapse formation	Late-stage	DISC1 4-bp deletion	Wen et al., 2014
	Fibroblasts	iPSC, differentiated to neural precursor cells	Increase of extramitochondrial oxygen consumption and ROS level	Abnormal metabolic changes during neurogenesis is associated with SZ	Late-stage	Clozapine resistant patient	Paulsen Bda et al., 2012

fSZ, familial schizophrenia; sSZ, sporadic schizophrenia; DG, dentate gyrus; TNF, tumor necrosis factor; ROS, reactive oxygen species.