Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca2+ entry and accelerated differentiation

Abstract

While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca2+) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca2+ entry (SOCE) is not well understood. Here, we report Ca2+ and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons. First, using a Ca2+ re-addition assay we found that BD-NPCs and neurons had attenuated SOCE. Intrigued by this finding, we then performed RNA-sequencing and uncovered a unique transcriptome profile in BD-NPCs suggesting accelerated neurodifferentiation. Consistent with these results, we measured a slower rate of proliferation, increased neurite outgrowth, and decreased size in neurosphere formations with BD-NPCs. Also, we observed decreased subventricular areas in developing BD cerebral organoids. Finally, BD NPCs demonstrated high expression of the let-7 family while BD neurons had increased miR-34a, both being microRNAs previously implicated in neurodevelopmental deviations and BD etiology. In summary, we present evidence supporting an accelerated transition towards the neuronal stage in BD-NPCs that may be indicative of early pathophysiological features of the disorder.

Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models

“…One showed a decrease in size of the subventricular zone in bipolar disorder organoids, compared with those derived from healthy donors. 152 In the other study, iPSC-derived human cortical spheroids of patients with bipolar disorder showed smaller size of spheroids, reduced proportion of neurons, reduced neural network activity, and decreased neuronal excitability compared with the 3D models obtained from healthy controls. 195 …”

“…Another study, using iPSCs from patients with bipolar disorder, showed further morphological alterations such as a decrease in the size of neurospheres and an increase in the length of their neurites. 152 However, a different study reported a decrease in the length of neurites and in the number of synapses in bipolar disorder–derived cells, compared with control iPSCs. 164 …”

“… 151 An increase in microRNA-34a levels was also recently observed in a study using NPCs from patients with bipolar disorder. 152 …”

“…An iPSC study showed that neurons derived from iPSCs of patients with bipolar disorder presented alterations in the expression of calcium membrane receptors and calcium influx dynamics, compared with cells derived from healthy controls. 152 Furthermore, 1 study analyzed RNA expression of NPCs produced from iPSCs of patients with bipolar disorder, showing both increases and decreases in expression of the different genes controlling the levels of calcium channels subunits. 140 Finally, 1 study with iPSCs showed that, in neurons derived from patients with bipolar disorder, a hyperactivity in calcium signalling can be recorded, compared with cells from healthy donors.…”

Early life stress-induced miR-708-5p affects bipolar disorder-associated phenotypes through neuronatin downregulation

“…However, ER calcium dynamics emerges as another major player. For example, store operated calcium entry (SOCE) is dysregulated in BD-induced pluripotent stem cells, leading to earlier neuronal differentiation and abnormal neurite outgrowth (81). Furthermore, altered expression of the miR-708-5p target Nnat has been associated with defective intracellular and ER calcium levels (33,74,82).…”