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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