Neuronal hyperexcitability is a hallmark of
seizures. It has been recently shown in rodent models of
seizures that microglia, the brain's resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interacts with human neurons to regulate hyperexcitability mediated by
epilepsy-causing genetic mutation found in human patients remains unknown. The SCN2A genetic locus is responsible for encoding the
voltage-gated sodium channel Nav1.2, recognized as one of the leading contributors to monogenic
epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation identified in patients with
epilepsy leads to hyperexcitability in a hiPSC-derived cortical neuron model from a male donor. While microglia play an important role in the brain, these cells originate from a different lineage (yolk sac) and thus are not naturally present in hiPSCs-derived neuronal culture. To study how microglia respond to diseased neurons and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display altered morphology with increased branch length and enhanced
calcium signal when co-cultured with neurons carrying the Nav1.2-L1342P mutation. Moreover, the presence of microglia significantly lowers the action potential firing of neurons carrying the mutation. Interestingly, we further demonstrated that the current density of
sodium channels in neurons carrying the
epilepsy-associated mutation was reduced in the presence of microglia. Taken together, our work reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an
epilepsy-causing mutation present in human neurons, highlighting the importance of neuron-microglia interactions in human pathophysiology.