Deficits in human trisomy 21 iPSCs and neurons

Results from induced pluripotent stem cell studies of neurogenesis are discordant: the generation of neurons from induced pluripotent stem cells has been reported in some studies to be impaired and in others not to be impaired, which may be explained by technical differences in the cell lines and protocols used.

“However, results from these studies are discordant: the generation of neurons from iPSCs has been reported in some studies to be impaired74,77–79 and in others not to be impaired75,80,81, which may be explained by technical differences in the cell lines and protocols used (see Box 1).”

Analyses of neural progenitor cells arising from trisomy 21 induced pluripotent stem cells have provided conflicting data, with some suggesting that apoptosis is increased and others seeing no effect.

“Analyses of NPCs arising from T21 iPSCs have provided conflicting data, with some suggesting that apoptosis is increased74,79,95 and others seeing no effect75,77,81,96.”

In T21 iPSC-derived neurons, the proportion of inhibitory to excitatory synaptic transmission does not differ from controls, contrary to findings in mouse models of DS.

“However, the proportion of inhibitory to excitatory synaptic transmission, as assessed by the number of inhibitory post-synaptic currents relative to the number of excitatory post-synaptic currents detected using whole-cell voltage clamp, does not differ between control and T21 iPSC-derived neurons, contrary to findings in mouse models of DS81.”

In vitro human iPSC-derived neurons from individuals with DS have reduced excitatory synaptic density relative to controls and functional deficits in excitatory synaptic transmission, including reduced frequency of spontaneous post-synaptic currents.

“In vitro data from human iPSC-derived neurons indicate that neurons from humans with DS not only have reduced excitatory synaptic density relative to controls but also exhibit functional deficits in excitatory synaptic transmission, including reduced frequency of spontaneous post-synaptic currents81,131.”

Genome-wide dysregulation of gene expression in neurons likely leads to over-expression and/or under-expression of key genes that regulate synaptogenesis.

“Genome-wide dysregulation of gene expression (Box 3) in neurons likely leads to over-expression and/or under-expression of key genes that regulate synaptogenesis, but specific candidates have yet to be identified74,77,81,143.”

Trisomic iPSC-derived early cortical neurons show decreased synapsin positive puncta and decreased incidence/frequency of spontaneous post synaptic currents.

“Recapitulating this finding, a study of iPSC derived early cortical neurons identified a decrease in synapsin positive puncta as well as a decrease in the incidence and frequency of spontaneous post synaptic currents, indicating deficits in the ability to form functional synaptic connections in trisomic neurons (Weick et al., 2013).”

Two studies found no changes in differentiation of excitatory cortical neurons from trisomic iPSCs.

“Two studies using isogenic pairs of iPSCs did not identify any changes in differentiation of excitatory cortical neurons (Weick et al., 2013; Murray et al., 2015).”

No change in electrical properties of trisomic early cortical neurons.

“One study found no change in the electrical properties of either excitatory or inhibitory trisomic early cortical neurons indicating that at that stage, there is no difference in intrinsic ability to communicate (Weick et al., 2013).”