From: Human stem cell-based models for studying autism spectrum disorder-related neuronal dysfunction
Genetic variant (syndrome) | Donor source | Differentiation approach | Neural derivative | Key phenotypic changes | References |
---|---|---|---|---|---|
FMR1 (Fragile X syndrome) | ESC | EF | Neurons (generic) | Decreased rise time and increased duration of action potentials and spontaneous synaptic currents Decreased frequency of action potential firing Lack of responsiveness to glutamate | [11] |
 | iPSC |  | NPCs Neurons (generic) | Decreased neurite length Augmented intracellular Ca2+ responses to AMPA and kainate mediated by Ca2+-permeable AMPARs that lack the GLUA2 subunit Increased proportion of Ca2+-permeable AMPAR and NMDAR-co-expressing progenitors Increased expression of miR-181a, which represses translation of GLUA2 transcripts | [51] |
 |  |  | Neurons (generic) | Increased expression of REST Several miRNAs dysregulated including hsa-miR-382 Downregulation of genes involved in axon pathfinding such as ROBO3, DCC and SLIT1 | [52] |
MECP2 (Rett syndrome) | ESC and iPSC | EF | Neurons (generic) | Decreased neurite outgrowth and dendritic arborization | [48] |
 | iPSC |  | Neurons (mixed) | Decreased neuronal soma size Decreased spine densities Decreased number of glutamatergic synapses (partially rescued by overexpression of MECP2 or IGF1 treatment) Decreased frequency of activity-dependent Ca2+ oscillations Decreased EPSC frequency | [53] |
 |  |  | Neurons (generic) | Decreased expression of KCC2 leading to a delayed GABA functional switch from excitation to inhibition | [54] |
 |  |  | Neurons (mixed) | Decreased neuronal soma size Decreased dendritic arborization Increased input resistance Decreased membrane capacitance Decreased action potential frequency | [57] |
 | iPSC |  |  | Decreased astrogenesis | [91] |
 | iPSC and ESC |  | Neurons (GABAergic) Astrocytes | Decreased neurite length and decreased number of terminal ends of wild-type interneurons after co-culture with mutant astrocytes Increased neurite length and increased number of terminal ends of mutant interneurons after co-culture with wild-type astrocytes | [92] |
 | iPSC |  | Organoids | Decreased thickness of the ventricular wall but increased ventricular areas Increased number of NPCs Reduced expression of neuronal markers | [134] |
CDKL5 | iPSC | EF | Neurons (generic) | Decreased number of excitatory synapses with aberrant spine structure | [60] |
15q11-q13: UBE3A (Angelman syndrome) | iPSC | EF | Neurons (mixed) | Impaired maturation of resting membrane potential Decreased action potential frequency Decreased spontaneous EPSC frequency and synaptic plasticity Decreased frequency of Ca2+ transients | [62] |
 | ESC, iPSC | FP | Neurons (glutamatergic, GABAergic) | Increased action potential frequency Increased amplitude of the fast components after hyperpolarization | [64] |
 | ESC | EF | Organoids | Increased action potential frequency Increased frequency and amplitude of Ca2+ transients |  |
15q11-q13 duplication syndrome | iPSC | EF | Neurons (mixed) | Delayed action potential maturation Increased frequency of spontaneous action potential firing Increased synaptic event frequency and amplitude Impaired activity-dependent synaptic plasticity and homeostatic synaptic scaling | [63] |
CACNA1C (Timothy syndrome) | iPSC | EF | Neurons (mixed) | Defects in intracellular Ca2+ signaling and activity-dependent gene expression Decreased fraction of neurons expressing lower cortical layer markers Abnormal expression of tyrosine hydroxylase Increased production of norepinephrine and dopamine Defects in action potential firing | [65] |
 |  |  | Spheroids | Increased Ca2+ levels following electrical depolarization Delayed interneuron migration (rescued by pharmacological modulation of L-type calcium channels) | [135] |
SHANK3 (Phelan-McDermid syndrome) | iPSC | EF | Neurons (mixed) | Decreased neuronal soma size Decreased growth cone area, neurite length and neurite branching Dysregulation of genes associated with neuron projection, motility and regulation of neurogenesis Defects in excitatory and inhibitory synaptic transmission | [68] |
 | ESC | FP | Neurons (glutamatergic) | Decreased neuronal soma size Decreased neurite length and branching Impaired Ih-channel function leading to increased neuronal input resistance and enhanced neuronal excitability Decreased EPSC frequency and amplitude | [69] |
 | iPSC | EF | Neurons (glutamatergic) | Decreased dendritic spine densities as well as whole spine and spine head volumes | [70] |
 | iPSC and ESC |  | Placodal neurons | Decreased neuronal soma size Increased neurite branching Decreased motility Decreased number of synaptic puncta | [71] |
 | iPSC |  | Neurons (glutamatergic) | Decreased number of synaptic puncta (rescued by IGF1 treatment) Increased input resistance Decreased amplitude and frequency of AMPA- and NMDA-EPSCs (rescued by SHANK3 expression) | [73] |
 | iPSC and ESC |  |  | Decreased intensities and frequencies of spontaneous Ca2+ oscillations (rescued by lithium and VPA treatment) | [181] |
EHMT1 (Kleefstra syndrome) | iPSC | FP | Neurons (glutamatergic) | Upregulation of GRIN1, encoding the NMDAR subunit 1 Decreased burst frequency and prolonged inter-burst interval (rescued by chronical treatment with the NMDAR channel pore blocker MK-801) Increased burst duration (rescued by chronical treatment with MK-801) Divergent spike organization with fewer spikes occurring outside network bursts Irregular network bursting (rescued by chronical treatment with MK-801) | [74] |
SHANK2 | iPSC | EF | Neurons (glutamatergic) | Increased dendrite length Increased number of synapses Upregulation of genes associated with neurodevelopment Compromised activity-dependent dendrite extension Increased EPSC frequency | [76] |
NLGN4 (R704C variant) | ESC | FP | Neurons (glutamatergic, GABAergic) | Increased number of excitatory synapses Increased miniature EPSC frequency | [77] |
NRXN1 | iPSC | EF | Neurons (glutamatergic) | Increased frequency, duration and amplitude of Ca2+ transients Dysregulation of genes associated with ion transport and transporter activity | [78] |
 | iPSC |  | NPCs Neurons (mixed) | Decreased NPC proliferation Increased astrogenesis Decreased amplitude and slower rise time of Ca2+ transients Decreased action potential amplitude | [79] |
 | ESC |  | Neurons (glutamatergic) | Increased levels of the critical synaptic scaffolding protein CASK Decreased miniature EPSC frequency | [80] |
 | iPSC |  | Neurons (mixed) | Decreased neuronal network activity | [81] |
 | iPSC and ESC |  | Neurons (generic) | Impaired astrocyte differentiation | [90] |
16p11.2 CNV | iPSC | EF | Neurons (generic) | Deletion Increased neuronal soma size Increased dendrite length and neurite branching Decreased number of synapses Decreased neuronal excitability Duplication Decreased neuronal soma size Decreased dendrite length and neurite branching Decreased number of synapses Increased neuronal excitability | [83] |
TRPC6 | iPSC | EF | NPCs Neurons (mixed) | Decreased neurite length (rescued by treatment with the TRPC6-specific agonist hyperforin and overexpression of TRPC6) Decreased neurite branching (rescued by treatment with hyperforin and overexpression of TRPC6) Decreased density of dendritic spines (rescued by treatment with hyperforin and overexpression of TRPC6) Decreased density of VGLUT1 puncta (rescued by treatment with hyperforin and IGF1 as well as overexpression of TRPC6) Decreased Ca2+ influx in NPCs Decreased Na+ current densities | [84] |
lncRNA PTCHD1-AS | iPSC | EF | Neurons (generic) | Decreased frequency of AMPAR-mediated miniature EPSCs Decreased NMDA-evoked current amplitude | [85] |
AFF2/FMR2 ANOS1 ASTN2 ATRX CACNA1C CHD8 DLGAP2 KCNQ2 SCN2A TENM1 | iPSC (isogenic) | FP | Neurons (glutamatergic) | Decreased capacitance: ATRX-, SCN2A-null neurons Increased action potential threshold: ATRX-, CHD8-, SCN2A-, TENM1-null neurons Decreased action potential amplitude: SCN2A-null neurons Decreased spontaneous EPSC frequency: AFF2-, ASTN2-, ATRX-, KCNQ2- and SCN2A-null neurons Decreased mean firing rate and network burst frequency: SCN2A-null neurons | [49] |
SETD5 ERP44 SKIV2L | iPSC | EF | Neurons (generic) Astrocytes | Decreased number of synapses Decreased glutamate release Decreased spontaneous neuronal spiking activity | [93] |
Unknown | iPSC | EF | Neurons (mixed) | Altered expression of 161 genes of which 22 have previously been associated to ASD Decreased Na+ and fast inactivating K+ voltage-gated currents Earlier action potential saturation Decreased spontaneous EPSC frequency and half width | [86] |
 |  |  | Neurons (glutamatergic) | Decreased Ca2+ transients Decreased spontaneous neuronal spiking | [87] |
 |  |  | NPCs Neurons (mixed) | Increased NPC proliferation correlating with the patients’ brain volumes (rescued by lithium chloride treatment) Increased number of inhibitory precursors and neurons (further facilitated by IGF1 treatment) Decreased number of glutamatergic precursors and neurons Decreased excitatory synapse density Decreased number of network bursts (rescued by IGF1 treatment) | [88] |
 |  | EF and FP | Neurons (generic, EF) Neurons (glutamatergic, FP) Organoids | Increased neurite length and branching observed in neurons derived in 2D by EF and in 3D organoids | [89] |
 |  | EF | Organoids | Upregulation of FOXG1 Altered expression of genes related to cell proliferation, differentiation and synaptogenesis Differentiation bias towards GABAergic phenotype (rescued by shRNA-mediated knockdown of FOXG1) | [129] |
CHD8 | iPSC | EF | Organoids | Upregulation of DLX genes associated with GABAergic interneuron differentiation | [130] |
 |  |  | NPCs Neurons (mixed) | Dysregulation of genes implicated in neural development | [131] |
 |  |  | NPCs | Downregulation of genes implicated in neuronal differentiation | [132] |
RAB39B | iPSC | EF | Organoids | Increased NPC proliferation Impaired differentiation of NPCs | [133] |