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Table 1 Cell biological and functional phenotypes revealed in 2D and 3D PSC-derived models of ASD

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]

  1. Neurons (generic): no subtype characterization provided; neurons (mixed): population includes multiple subtypes; neurons (glutamatergic): population predominantly consisting of glutamatergic neurons
  2. EF extrinsic factor-guided differentiation, FP forward programming