Single-cell multiomics data analysis of potential receptors and therapeutic drugs for epilepsy patients comorbid with depression

Abstract

Depression frequently cooccurs with epilepsy (EP) and has become a focus of clinical management, but effective pharmacological interventions remain limited. In this study, single-cell RNA sequencing (scRNA-seq) data were analyzed to identify changes in oligodendrocyte precursor cells (OPCs) in EP and major depressive disorder (MDD) patients, and intercellular communication and trajectory analyses were performed. Key therapeutic targets and pathways were identified via differentially expressed genes (DEGs), protein-protein interaction (PPI) networks, and gene ontology (GO) enrichment. A connectivity map (CMap) was generated to identify optimal drugs. Molecular dynamics simulation (MDs) and cell thermal stability migration assay (CETSA) were conducted to evaluate protein-drug interactions. The results revealed significant changes in gene expression in OPCs, with neuroligin3 (NLGN3)-neurexin (NRXN) signaling being the main pathway involved. Three hub genes correlated with NLGN3 were enriched in oxidative phosphorylation and mTORC1 signaling. Ziprasidone could effectively treat EP with MDD by strongly binding to NLGN3, forming two hydrogen bonds with a binding energy of −7.5 kcal/mol. This stable interaction was further confirmed by MDs and CETSA experiments. In conclusion, the NLGN3 protein interacts with ziprasidone to form stable complexes, which may activate the NLGN3-NRXN signaling pathway in OPCs and enhance synaptic remodeling by reducing neuroinflammatory responses.