Using Human iPSC-Derived Neurons to Uncover Activity-Dependent Non-Coding RNAs

Humans are arguably the most complex organisms present on Earth with their ability to imagine, create, and problem solve. As underlying mechanisms enabling these capacities reside in the brain, it is not surprising that the brain has undergone an extraordinary increase in size and complexity within the last few million years. Human induced pluripotent stem cells (hiPSCs) can be differentiated into many cell types that were virtually inaccessible historically, such as neurons. Here, we used hiPSC-derived neurons to investigate the cellular response to activation at the transcript level. Neuronal activation was performed with potassium chloride (KCl) and its effects were assessed by RNA sequencing. Our results revealed the involvement of long non-coding RNAs and human-specific genetic variants in response to neuronal activation and help validate hiPSCs as a valuable resource for the study of human neuronal networks. In summary, we find that genes affected by KCl-triggered activation are implicated in pathways that drive cell proliferation, differentiation, and the emergence of specialized morphological features. Interestingly, non-coding RNAs of various classes are amongst the most highly expressed genes in activated hiPSC-derived neurons, thus suggesting these play crucial roles in neural pathways and may significantly contribute to the unique functioning of the human brain.