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Table 4 Connectivity and circuitry dysfunction observed in published human iPSC models of neurological diseases

From: Connectivity and circuitry in a dish versus in a brain


iPSC-derived cell types

Observed phenotypes


Alzheimer’s disease

Cortical neurons

• Accumulated extracellular Aβ oligomers inside familial and sporadic neurons, leading to oxidative stress

[78, 133135]


• Selectively decreased glutamatergic neurons rather than GABAergic neurons with increasing concentrations of the globulomeric form of Aβ42


• Redistributed hyperphosphorylated tau to the somatodendritic compartments


Amytrophic lateral sclerosis

Motor neurons, astrocytes

• Hyperexcitability of amytrophic lateral sclerosis patient-derived motor neurons

[138, 139]


• Kv7 channel-activator retigabine could revert motor neuron hyperexcitability


• Astrocytes from amytrophic lateral sclerosis patient-derived iPSCs show toxicity towards motor neurons in co-culture


Dravet syndrome

Glutamatergic and GABAergic neurons

• Impaired action potential generation in GABAergic neurons derived from Dravet syndrome patient tissue

[106, 140, 141]


• Hyperexcitability and spontaneous epileptic action potential firing in glutamatergic neurons


• Increased sodium currents


• Hyperexcitability was reduced after treatment with phenytoin


Down syndrome

Cortical neurons

• Defected the ability to form functional synapses in early trisomy of chromosome 21 iPSC neurons

[90, 142]


• Diminished number of neural progenitor cells associated with a proliferation deficit and increased apoptosis.


• Reduced number and length of neurites from soma of neurons


• Decreased frequencies of spontaneous neurotransmission, affecting excitatory and inhibitory synapses equally


Fragile X syndrome

NPCs, neurons of unspecified subtype

• Impaired neuronal differentiation of Fragile X syndrome patient-derived iPSCs

[143, 144]


• No clear effect on glial differentiation


• No activation of mutant FMR1 locus during iPSC generation from Fragile X syndrome patient tissue


Parkinson’s disease

Dopaminergic neurons

• Reduced numbers of neurites and neurite arborization

[136, 137]


• Decreased dopamine uptake and disrupted the precision of dopamine transmission by increasing spontaneous dopamine release



Glutamatergic neurons

• Elevated levels of secreted catecholamines including dopamine, norepinephrine, and epinephrine secretion

[88, 91]


• Increased percentage of tyrosine hydroxylase-positive neurons, the first enzymatic step for catecholamine biosynthesis


• Decreased neuronal connectivity and numbers of neurites


Spinal muscular atrophy

Motor neurons

• Attenuated levels of SMN1 protein in spinal muscular atrophy iPSC neurons, resulting in the selective degeneration of motor neurons

[96, 145]


• Decreased numbers of motor neuron survival with a reduced size


• Reduced axonal growth and neuromuscular junction formation


Rett syndrome

Glutamatergic neurons

• Diminished number of synapses and dendritic spines



• Abnormally decreased activity-dependent calcium oscillations


• Reduced frequencies and amplitude of spontaneous synaptic currents, reflecting fewer release sites or a decreased release probability of neurotransmission


Phelan–McDermid syndrome

Forebrain neurons

• Impaired excitatory neurotransmission indicated by reduced amplitudes and frequencies of spontaneous excitatory postsynaptic currents



• Disrupted the ratio of cellular excitation and inhibition in Phelan–McDermid syndrome neurons

  1. Aβ, amyloid beta; GABA, γ-aminobutyric acid; iPSC, induced pluripotent stem cell; NPC, neural progenitor cell