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

Alzheimer’s disease

Cortical neurons

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

[78, 133–135]

• 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

Schizophrenia

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

[87]

• 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

[89]

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