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Figure 1. Schematic overview of the potential and utility of induced pluripotent stem cell (iPSC) in precision medicine. In the first step the
likely pathogenic variant is identified using, e.g., next-generation sequencing technologies with DNA isolated from peripheral blood. In
case of a variant without a known function loss-of-function or gain-of-function and/or for drug screening, primary fibroblast cultures are
established from patient skin biopsies and reprogrammed into human induced pluripotent stem cell (hiPSC). The pathogenic variant can
then be corrected using CRISPR/Cas9 gene editing, which generates isogenic controls for the patient hiPSCs with the pathogenic variant.
Both hiPSCs are subsequently differentiated into relevant neurons (gluatamatergic or GABAergic in case of monogenic epilepsies) or
cerebral organoids, which can be used in electrophysiological studies to determine the functional consequences and/or in drug screening

in parallel to record and measure spontaneous firing of action potentials of neuronal networks. MEA has
effectively been used for different approaches in epilepsy studies, such as predicting seizure liability at the
early stage of preclinical studies, drug screening and drug safety [36,37] . Recently, utilizing MEA in combination
with in vitro hiPSC models has effectively been applied to drug screening studies such as frequency analysis,
revealing prediction of toxicity and side effects of anticonvulsants and their mechanism of action. In
addition, it has been demonstrated that hiPSC-derived astrocytes and neuron co-cultures mimic in vivo
conditions better than monocultures of neurons. These observations suggest that such experimental setup
[38]
may be considered suitable for toxicity prediction .
MEAs are generally easy to handle in terms of cell types in the cultures and reproducibility. Although,
patient-derived neurons are investigated, the MEA system cannot achieve the complexity needed to
understand the pathophysiology and cell type-specific communication between different types of neurons,
astrocytes and oligodendrocytes in the brain. In contrast, MEA analyses of neurons could potentially be
useful for large scale drug screening to investigate if certain drugs/compounds could restore abnormal
[37]
network activity in neurons. The use of MEAs in drug screening in epilepsy is still in its infancy and more
studies are needed before MEAs can be used as a high-throughput screening platform for personalized
medicine.

IPSC-DERIVED NEURONAL CULTURES
Cell types used in hiPSC programming
Epilepsy models based on hiPSC technology have the potential to be a revolutionary platform for functional
studies, and as drug screening and discovery tools. Figure 1 illustrates the overview of the potential of
hiPSC in relation to epilepsy. The most common cell type in generating hiPSCs is skin fibroblasts cultured