Human cerebral spheroids undergo 4-aminopyridine-induced, activity associated changes in cellular composition and microrna expression

Activity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of 4-aminopyridine (4AP) on neuronal activity and associated neurogenesis. Our studies demonstrate that 4AP increases neuronal activity in 3-month-old cerebral spheroids while increasing numbers of new neurons and decreasing the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study several aspects of activity-induced neurogenesis.

Automated summary

Activity-induced neurogenesis has been widely studied in rodents but less in humans. In this study, neuronal activity and associated neurogenesis were investigated in cerebral spheroids derived from human induced pluripotent stem cells (iPSCs). The results show that 4AP increases neuronal activity, promotes the generation of new neurons, and reduces the number of new glial cells. Furthermore, the expression of miR-135a, a key regulator of exercise-induced neurogenesis, was significantly decreased, suggesting its involvement in the process. These findings highlight the potential of iPSC-derived cerebral spheroids as a model for studying activity-induced neurogenesis.