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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

Disease iPSC-derived cell types Observed phenotypes References
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  
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  
  1. Aβ, amyloid beta; GABA, γ-aminobutyric acid; iPSC, induced pluripotent stem cell; NPC, neural progenitor cell