Seizure susceptibility relates to microglial TREM2 expression and morphology in a multiple repeated low-dose kainic acid model

Microglia, the resident immune cells of the brain, play a critical role in maintaining homeostasis. In this study, we investigated changes in microglial phenotype associated with seizure susceptibility. Kainic acid (KA) was injected intraperitoneally, and when seizures reached Racine stage 4/5, administration was stopped, and mice were monitored for 60 min. Only mice that showed behavioral convulsive status epilepsy (SE) in the first experiment received a second KA injection 2 weeks later. Using this model, we observed changes in brain tissue and microglial phenotype according to seizure susceptibility. We also analyzed gene expression patterns associated with microglial phagocytosis in a publicly available hippocampal transcriptome microarray dataset (GSE88992) from mice injected with KA. After the initial low-dose KA repeat injection, the number of injections required to induce SE during the secondary injection was compared with the initial injection, and mice were categorized into seizure-resistant (SR, n = 26, no SE), seizure-tolerant (ST, n = 11, SE after ≥2 injections), and seizure-susceptible (SS, n = 15, SE after ≤2 injections) groups. Neuronal loss was observed in all seizure groups, but the extent varied across hippocampal regions. Microglial phenotypes in the hippocampus showed significant differences between groups. Immunofluorescence staining further confirmed that triggering receptor expressed on myeloid cells (TREM2) expression was increased in microglia in the SS group. Using a model that classifies seizure resistance, tolerance, and susceptibility, we observed significant differences in microglial phenotypes and TREM2 expressions between groups. This study highlights the role of microglia in the progression from first seizures to subsequent seizures, a critical step in the development of epilepsy.