Skip to main content

Table 1 Summary of studies using in vitro model to study ASD

From: Human in vitro models for understanding mechanisms of autism spectrum disorder

Mutation typeStudyGene/SyndromeNumber of individuals (ASD/Control)Isogenic?ProliferationCell deathNeuronal differentiationElectrophysiological properties
IdiopathicMariani et al. [59]Idiopathic with macrocephaly4/8NoDecreased cell-cycle length in NPCs and early stages of neuronal differentiationNAIncreased MAP2 in neurons
More synaptic puncta
Increased proportion of GABAergic neurons
Reduced peak sodium current
Liu et al. [115]Idiopathic (no seizures or ID)3/3NoNANANo change in cell proportions
No difference in the number of primary neurites
Reduced sEPSC frequency and half width while amplitude and rise time were not changed
Decreased Na+ and fast K+ voltage-gated currents
Marchetto et al. [60]Idiopathic with macrocephaly8/5NoNPCs proliferated fasterNAReduced proportion of BRN2+ and NGN2+ cells
Increased proportion of GABAergic cells
Fewer excitatory glutamatergic synapses
Reduced maturation
No difference was observed in the frequency of spontaneous action potentials
Reduced number of synchronized bursts
No increase in the number of spikes with maturation
Russo et al. [116]Idiopathic (without seizures)3/3NoNo differences in proliferationNANo change in cell proportions
Reduced synaptogenesis as an interaction between astrocytes and neurons
Decreased spontaneous spike rate
DeRosa et al. [112]Idiopathic5/5NoNANANAFewer spontaneous spikes
Fewer spontaneous calcium transients
Griesi-Oliveira et al. [113]Idiopathic13/8NoNANANANA
Schafer et al. [114]Idiopathic8/5NoNANAAcceleration differentiation of neurons
More complex neurite branching patterns
NA
Lewis et al. [143]Idiopathic1 multiplex family - 1 affected individual/1 intermediate phenotype relative/1 unaffected relative and 1 unaffected controlNoNo changes in cell cycleIncreased apoptosis of both excitatory and inhibitory neuronsDEG were enriched for GO terms related to neuron differentiationNA
Moore et al. [118]Idiopathic3/3NoIncreased proliferationNADecrease in the proportion of neurons
Shorter neurites
NA
Adhya et al. [117] preprintIdiopathic/NRXN1/3p deletion syndrome6/2/1/3 controlsNoUpregulation of genes associated with cell proliferationUpregulation of genes associated with regulation of apoptosisDelayed neuronal maturation
Fewer excitatory and inhibitory NPCs but more GABAergic neurons
NA
Wang et al. [119]Idiopathic with macrocephaly (subset of [60])3/3NoIncreased proliferation leading to an increase in double stranded breaksNoDecreased cell migration
Defects in polarity and adherence junctions
NA
Griesi-Oliveira et al. [120]Idiopathic6/6NoUpregulation of genes associated with cell proliferation in NPCsNAUpregulation of genes associated with synapse and neurotransmitter release
Shorter neurites with fewer ramifications
NA
 Deshpande et al. [125]16p11.2 deletion and duplication3 deletion/3 duplication/4 controlNoNo changes in proliferationNA16p11.2 deletion neurons have increased total dendrite length and more extensive dendritic arbors compared with controls
The 16p11 duplication neurons exhibit the opposite phenotype with significantly reduced total dendrite length
Lower density of synaptic puncta, in both 16p11.2 deletion and 16p11.2 duplication
Reduced excitability in 16p11.2 deletion
No difference in the kinetics or frequency of the mEPSCs in 16p11.2 deletion and 16p11 duplication neurons
CNVLin et al. [144]22q11.2 deletion (DiGeorge syndrome)8/7NoDownregulated DEGs were enriched for cell cycle GO terms
Decreased proliferation
Upregulated DEGs were enriched for apoptosisNANA
Toyoshima et al. [124]22q11.2 deletion (DiGeorge syndrome)2/3NoSmaller neurospheresNAThe fraction of neurons was reduced while the fraction of astrocytes was increased
Shorter neurites
 
Fink et al. [122] preprintDup15q syndrome (15q11-q13 duplication)
Angelman syndrome (15q11-q13/UBE3A maternal deletion)
15q11-q13 paternal duplication
4 Dup15q/3 Angelman syndrome/1 paternal duplication/6 controlsNoNANo change in cell death in Dup15qNo differences in dendritic complexity in Dup15q
Decrease dendritic complexity in Angelman syndrome
Delayed maturation of action potential
Increased frequency and amplitude of synaptic events
Increased frequency of spontaneous firing of action potentials
Fink et al. [121]Angelman syndrome (15q11-q13/UBE3A maternal deletion)3/4YesNANo change in cell deathNo changes in cell proportionsImpaired maturation of resting membrane potential
Decreased spontaneous excitatory synaptic activity
Gillentine et al. [126]CNRNA7(15q13.3 deletion) deletion and duplication3 duplication/3 deletion/3 controlNoNANANADecreased α7 nAChR-associated calcium flux in both deletions and duplications
Deneault et al. [145]16p11.2 deletion, Nrxn1, DLGAP, CNTN5, AGBL4, GLI, CAPRIN, VIP, ANOS1, EHMT2, THRA, SET53 lines from 26 individuals 15 ASD/11 control (1 individual from each, 2 Mz from SET)YesNANANAIncreased neuronal activity in glutamatergic neurons with CNTN5 or EHMT2 mutations
Single genePasca et al. [142]CACNA1C (Timothy syndrome)2/3NoNANADecreased fraction of neurons expressing lower-layer markers and an increased fraction of neurons expressing upper-layer markers.
More neurons expressed tyrosine hydroxylase (TH) which was not caused by shift in cell fate
No differences in the action potential threshold or amplitude, resting membrane potential, input resistance or capacitance
Wider action potentials
Increase in the sustained Ca2+ rise after depolarization
Wang et al. [131]CHD81 individual
2 control lines/4 heterozygous lines (Crispr)
YesNANADEG were enriched for neurogenesis, neuronal differentiation and forebrain developmentNA
Sugathan et al. [132]CHD8 (knockdown)1 individualYesNANADownregulated DEG were enriched for synapse formation and neuron differentiationNA
Frega et al. [139]EHMT1 (Kleefstra syndrome)3/3YesNANANo difference in dendritic morphology or synaptic densityNo differences in AMPA-related mEPSCs
Fewer, less regular, and longer network bursts which were caused by NMDAR activity
Marro et al. [138]NLGN41 ES line/1 knockout line/1 mutant lineYesNANAIncreased number of excitatory synapses in mutant lineIncreased frequency and amplitude of mEPSCs in mutant line
Zeng et al. [134]NRXN11 ES line/1 iPSC lineYesNANADownregulation of astrocyte differentiation
DEG were enriched for neuron differentiation-related GO terms
NA
Pak et al. [133]NRXN12 induced mutations in 1 lineYesNANANo changes in differentiation
No changes in synaptic density
No change in the number if readily releasable pool of vesicles
No change in intrinsic membrane properties
Decreased frequency of spontaneous mEPSCs
Impaired evoked neurotransmitter release
Lam et al. [135]NRXN11/4NoSlower proliferationNADecreased excitatory neuronal maturation
Higher proportions of astroglia
Action potentials had lower amplitude and lower rise time
Lower calcium concentration in response to depolarization
Avazzadeh et al. [136]NRXN13/5NoNANANo difference in cell proportionsIncreased frequency, duration, and amplitude of calcium transients associated with action potentials
Flaherty et al. [137]NRXN14/4YesNANADecreased proportion of mature neurons
Decreased neurite number and length
Decrease in the number of spontaneous action potentials (using two maturation methods)
Ross et al. [140]PTCHD1-AS2/2YesNo changes in proliferationNAIncreased number of synapses in one of the subjects and decreased dendrite complexity in the otherNo changes in membrane potential
Decreased frequency of mEPSCs
Decreased NMDA-evoked current amplitude
Zaslavsky et al. [146]SHANK22/4YesDownregulation of cell cycle genesNAIncreased synapse numbers, dendrite length, and neuron complexity
Increased number of functional excitatory connections
Increased sEPSC frequency
Yi et al. [127]SHANK31 lineYesNANADecrease length and branching of neurites
No change in the density or size of synapses
Increased input resistance with no change in capacitance
Decreased evoked excitatory postsynaptic currents
Decreased amplitude of spontaneous miniature EPSCs
Hyperexcitability caused by impaired Ih currents
Kathuria et al. [128]SHANK32/3
1 ES line
YesNANASmaller cell soma and more primary neurites in olfactory placodal neurons but not in cortical neurons
Shorter neurites in cortical neurons
NA
Gouder et al. [129]SHANK34/3NoNANAReduced dendritic spine densities and spine volumeNA
Huang et al. [130]SHANK32 linesYesNANAReduced neuronal soma size, neurite length, and neurite branch numberReduced frequency of sEPSC
Sun et al. [141]UBE3A (Angelman’s syndrome)1 ES cell lineYesNANANo changes in neuron morphologyIncreased firing frequency of action potentials
Increased synchronization
Deneault et al. [147]Many genes (isogenic) AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM11 control individual/1 lineYesNANANAReduced sEPSCs and in 5 out of 10 mutations often (4 out of 5 mutations) accompanied by reduced burst frequency
  1. Abbreviations: DEG differential expressed genes, EPSC excitatory postsynaptic current, sEPSC spontaneous excitatory postsynaptic current, mEPSC miniature excitatory postsynaptic current, NPC neuron precursor cell