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, 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 |