SnRNA-seq reveals seizure-induced remodelling of excitatory and inhibitory neuron populations

Epilepsy is one of the most common chronic neurological disorders. This study aimed to identify hippocampal neuronal subpopulations with the most prominent transcriptional alterations during the latent period following status epilepticus, thereby elucidating early molecular mechanisms of epileptogenesis in a pilocarpine-induced model. Status epilepticus (SE) was induced in male C57BL/6 N mice via intraperitoneal pilocarpine injection, and hippocampal tissue was collected on Day 7 post-SE (n = 3 per group) for single-nucleus RNA sequencing using a 10× Genomics platform. Data were processed using Seurat, clustered via UMAP, and analysed for differential gene expression and KEGG pathway enrichment. From 76,412 high-quality nuclei, we identified 45,584 excitatory neurons, 5,897 inhibitory neurons, and major glial subtypes. Dentate gyrus (DG) excitatory neurons exhibited the most profound transcriptional remodelling, segregating into control-enriched (DG1) and epilepsy-enriched (DG2) factions. The expression of Sorcs3, Rgs6, and Galntl6 was upregulated in DG2 neurons, whereas the expression of Trpc5, Itpr1, and Calb1 was upregulated in DG1 neurons. Among inhibitory neurons, Meis2-expressing interneurons showed the greatest change in relative abundance, with the Meis2-1 subtype tending to increase in relative abundance post-SE compared to controls (P = 0.0728, not significant) and selectively expressing the seizure-related genes Cpa6, Ano1, and Ano2. DG excitatory neurons and Meis2-positive inhibitory neurons represent the most prominently altered hippocampal cell types following seizures, highlighting their potential role in epileptogenic network reorganization. The identification of disease-specific molecular signatures within these populations provides a prioritised framework for investigating causal mechanisms and developing cell type-targeted therapeutic strategies for precision epilepsy treatment.