While iPSC‐derived neuronal studies can reveal insights into the functional changes associated with genomic variants, there are some limitations inherent in the use of these models. Studies suggest that the transcriptomes of human neurons and astrocytes derived from iPSC are more similar to fetal than to mature adult cells. 63 , 64 , 65 In the study of KCNJ6 variants, only a sub‐cluster of individual cells expressed markers consistent with functional neurons. 39 Several strategies are likely to improve cell maturation, such as the optimization of the culture media composition, 66 the combination of transcription factor‐based differentiation strategies with directed patterning, 67 and the use of longer term cultures. 68 The latter would be particularly suitable in the case of human iPSC‐derived glutamatergic neurons, which have shown increased expression of NMDA glutamate receptors and consequent increased synaptic activity in older neuronal cultures. 67 Another effective strategy is the co‐culture of neurons with supporting cells, such as human astrocytes or primary mouse astrocytes. 28 , 39 This co‐culture approach promotes not only maturation, but also synchronization of neuronal activity. 68 ,
