Microglia-Impaired Phagocytosis Contributes to the Epileptogenesis in a Mouse Model of Dravet Syndrome

Dravet syndrome (DS) is a genetic disorder caused by a deficit in the Nav1.1 channel, leading to drug-resistant epilepsy. The Nav1.1 channel plays a crucial role in microglial cell activation, and microglia are recognized as key mediators of seizures. In this study, we explored the role of microglia in DS-related epileptogenesis using a knock-in mouse model (<i>Scn1a^E1099X/+</i>) that mimics a subset of DS patients. In these DS mice, we observed a significant downregulation of the Nav1.1 channel in microglia. This channel deficit led microglia to adopt a pro-inflammatory state in their quiescent phase. In the LPS-activated state, microglia predominantly exhibited an intermediate morphology rather than the expected fully activated form. The reduced expression of pro-inflammatory cytokines was detected in microglia following treatment with LPS. Notably, we found a significant decrease in the phagocytic ability of microglia in DS mice. Electrophysiological studies revealed an increased immature synaptic activity in the dentate gyrus in DS mice. The impaired microglial phagocytosis of damaged cells, combined with reduced cytokine secretion, may result in an excess of immature synaptic connections, neuronal hyperexcitation, and the formation of abnormal neural circuits in the hippocampus of <i>Scn1a^E1099X/+</i> mice. These changes could potentially contribute to mechanisms relevant to epileptogenesis in DS.