Table 3 Etiologically valid cellular models of schizophrenia.
Risk variant in human | Model type | Differentiation | Zygosity | N (Case) | N (Control) | Ref. number | First author | Year | Molecular phenotypes | Cellular/circuity phenotypes | Other findings |
|---|---|---|---|---|---|---|---|---|---|---|---|
22q11.2 deletion | Patient-derived | Neurosphere | Heterozygous | 2 | 4 | 94 | Toyoshima M. | 2016 | • Downregulation of miR-17/92 and miR-106a/b clusters | • Reduction of neurosphere size, neural differentiation, neurite outgrowth, cellular migration, and neurogenic-to-gliogenic competence ratio | |
Patient-derived | NPC, 2D-neurons | Heterozygous | 8 | 7 | 95 | Lin M. | 2016 | • Upregulation of genes related to apoptosis/programmed cell death and downregulation of synaptic, cell cycle, and microtubule organization genes | • Lower NPC-proliferation rates | ||
Patient-derived | Cerebral cortical organoids | Heterozygous | 15 | 15 | 96 | Khan TA. | 2020 | • Altered expressions of neuronal excitability-related genes • Enrichment of schizophrenia heritability in DEGs of mature organoids | • Deficits of neuronal excitability and calcium signaling | • Recapitulation of calcium and membrane potential alterations in DGCR8+/- neurons • Rescue by DGCR8 restoration or an antipsychotic, raclopride | |
Patient-derived | iPS, NPC, 2D-excitatory neurons | Heterozygous | 20 | 29 | 97 | Nehme R. | 2022 | • Enrichment of schizophrenia genetic risk and synaptic genes in upregulated DEGs of NPCs and neurons | • Lower spiking rate of neurons in multi-electrode array analysis | ||
16p11.2 deletion/duplication | Patient-derived | 2D-cortical neurons | Heterozygous | 3 deletion 3 duplication | 4 | 98 | Deshpande A. | 2017 | • Increased and decreased soma area/dendritic length in 16p11.2 deletion and duplication, respectively • Reduction of synaptic density in both deletion and duplication | ||
Patient-derived | Cortical organoids | Heterozygous | 6 deletion 8 duplication | 4 | 99 | Kostic M. | 2021 | • A larger number of DEGs in 16p11.2 deletion than in duplication • Downregulation of neuron projection morphology-related genes and upregulation of positive chemotaxis genes in the deletion lines • Perturbation of genes regulated by RBFOX1 in the deletion lines | • Similar cell composition across organoids derived from 16p11.2 CNV carriers (deletion or duplication) and controls as revealed by scRNA-seq | ||
Patient-derived | Cortical organoids | Heterozygous | 3 deletion 3 duplication | 3 | 100 | Urresti J. | 2021 | • Enrichment of “ligand-gated ion channel activity” genes in DEGs of 16p11.2 deletion • No enrichment of GO terms in DEGs of 16p11.2 duplication | • Accelerated neural maturation in 16p11.2 deletion than in duplication • Increased synaptic puncta in 16p11.2 deletion • Neuronal migration deficits in both 16p11.2 deletion and duplication | • Rescue of migration deficits by inhibition of RhoA activity | |
CRISPR/Cas9 | 2D-dopaminergic neurons | Heterozygous | 3 deletion 3 duplication | 3 | 101 | Sundberg M. | 2021 | • Increased synaptic marker expression in 16p11.2 deletion lines • Reduced synaptic marker expression in 16p11.2 duplication lines | • Increased soma size in 16p11.2 deletion • Deficits in neuronal differentiation in 16p11.2 deletion | • Hyperactive DA neuronal networks and increased bursting in 16p11.2 deletion | |
CRISPR/Cas9 | 2D-neurons and cerebral organoids | Heterozygous | 7 deletion 6 duplication (in the 2D-neuron assay) | 6 clones (in the 2D-neuron assay) | 102 | Tai DJC. | 2022 | • Only nine DEGs in 16p11.2 deleted 2D-neurons while 95 DEGs in duplicated neurons • Enrichment of energy metabolism-related genes in DEGs of 16p11.2 duplicated 2D-neurons | • Shortened neurites with reduced branchpoints in both 16p11.2 deleted and duplicated 2D-neurons • Reduced activity, synchrony, and oscillation in 2D-neurons | • Altered proportion of the cell components of cerebral organoids in 16p11.2 deletion (i.e., decreased excitatory neurons and increased inhibitory GABAergic neuron) (2 clones per genotype in the cerebral organoid assays) | |
2p16.3 (NRXN1) deletion | Deletion of exon 19 shared by all neurexin-1 isoforms or insertion of premature stop codon just before the last exon by Cre-loxP/FLP-FRT in human ES cells | 2D-excitatory cortical neurons | Heterozygous | 1 (exon 19 deletion) 2 (premature stop codon) | 1 (exon 19 deletion) 2 (premature stop codon) | 103 | Pak C. | 2015 | • Normal neuronal morphology • Decreased spontaneous mEPSC frequency • Iimpaired neurotransmitter release | ||
Patient-derived | 2D-neurons | Heterozygous | 2 (5’-NRXN1a+/-) 2 (NRXN1a/b+/-) | 4 (including a family member of NRXN1α/β+/- carrier) | 104 | Flaherty E. | 2019 | • Enrichment of genes related to transcriptional/epigenetic regulation and schizophrenia GWAS-associated genes in DEGs of patient-derived NPC and neurons | • Reduced spontaneous neuronal activity in multi-electrode array analysis | • Comprehensive cataloging of a total of 123 high-confidence in-frame human NRXN1α isoforms | |
Patient-derived | 2D-neurons resembling cortical layer 2/3 pyramidal neurons | Heterozygous | 3 carrier-derived | 3 non-carrier-derived | 105 | Pak C. | 2021 | • No consistent differences between carrier- and non-carrier-derived neurons in principle component analyses of the data of bulk-RNA-seq • Upregulation of intracellular NRXN1-binding protein CASK in patient-derived iPS-neurons | • No change in dendritic and synaptic morphologies • Decrease in the frequency of spontaneous excitatory synaptic events, in evoked excitatory synaptic transmission, and in paired-pulse depression | ||
SETD1A LOF/PTV | CRISPR/Cas9 (heterozygous frameshift deletion in exon 7) | 2D-neurons | Heterozygous | 2 clones | 1 clone | 106 | Wang S. | 2022 | • Perturbation in gene sets associated with glutamatergic synaptic function • Increased cAMP signaling | • Increase of dendritic length and arborization, network burst activity, and synaptic integration |
