Table 4.

Selected studies investigating autism spectrum disorder using iPSCs from patients.

iPSC Model (s)	Observation (s)	Implication (s)	References
The iPSCs differentiated to NPCs and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size	The ASD-derived NPCs display faster proliferation than control-derived NPCs due to dysregulation of a β-catenin/BRN2 transcriptional cascade	Abnormal neurogenesis and synaptogenesis leading to functional defects in neuronal networks that could be rescued by the neurotrophic factor IGF-1	Marchetto et al. [76]
The iPSCs from ASD with macrocephaly differentiated to NSCs; iPSCs directly converted into iNs; generation of cerebral organoids	Dysregulation of specific transcriptional networks that caused aberrant neuronal maturation of ASD cortical neurons	The ASD-associated neurodevelopmental aberrations are triggered by a pathological priming of gene regulatory networks during early neural development	Shafer et al., 2019 [77]
Organoids derived from ASD-iPSCs	The ASD-derived organoids exhibit an overproduction of GABAergic inhibitory neurons, due to the overexpression of the transcription factor FOXG1	Cortical organoids of ASD patients show exuberant GABAergic differentiation and no change in glutamate neuron types, which together cause an imbalance in glutamate/GABA neuron ratio	Mariani et al., 2016 [78]
The iPSCs from ASD without macrocephaly differentiated to cortical and midbrain neurons	The ASD-iPSCs differentiated to cortical neurons displayed impaired neural differentiation. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, in contrast to previous studies	Patients with ASD but without macrocephaly exhibited impairments in neurogenesis compared with those from neurotypical individuals	Adhya et al., 2021 [79]
The NPCs derived from FMR1-knockout iPSCs as a model for studying FMRP functions and FXS pathology	Altered expression of neural differentiation markers, MRP-deficient neurons showed less spontaneous calcium bursts, corrected by the protein kinase inhibitor LX7101	Loss of FMRP resulted in abnormal differentiation accompanied by impaired neuronal activity	Sunamura et al. [80]
Both 2D and 3D FXS models based on isogenic FMR1 knock-out mutant and wild-type human iPSC lines	Cortical neurons derived from FMRP-deficient iPSCs exhibit altered gene expression and impaired differentiation when compared with the healthy counterpart	The FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in the developing brain	Brighi et al. [81]
Human SH-SY5Y neuroblastoma cells and FXS fibroblast-derived iPSCs	The FMRP deficiency results in hyperactivated nonsense-mediated mRNA decay (NMD). The key NMD factor UPF1 binds directly to FMRP, promoting FMRP binding to NMD targets	The FMRP acts as an NMD repressor. In the absence of FMRP, NMD targets are relieved from FMRP-mediated repression. Many abnormalities in FMRP-deficient cells are attributable, either directly or indirectly, to misregulated NMD	Kurosaky et al. [82]

ASD: Autism Spectrum Disorder; FXS: Fragile X syndrome; NSCs: neural stem cells; iNs: induced neurons; IGF-1: insulin-like growth factor 1; FMRP: fragile X mental retardation protein.