Cross-species transcriptomic analysis of rodent model fidelity to human mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is a common form of drug-resistant epilepsy, necessitating reliable rodent models for translational research. Although numerous rodent models reproduce hippocampal epileptogenesis, their molecular fidelity to human MTLE remains unclear. In this study, we conducted an integrative analysis of human MTLE transcriptomic data and evaluated rodent epilepsy models by comparing their transcriptomic profiles with those of human MTLE. By integrating 694 human samples (mean age 39.6 years, 40.3% female, 12 datasets) and 362 rodent samples (postnatal and adult mice and rats, 13 datasets), we identified synaptic dysfunction alongside elevated neuroinflammation and gliogenesis in chronic drug-resistant MTLE. Subsequent cross-species correlation analysis revealed that the intrahippocampal kainate-induced model best mimicked MTLE with hippocampal sclerosis (HS), characterized by neuroinflammation and gliogenesis. In contrast, the perforant path stimulation-induced model exhibited a high correlation with MTLE without HS, highlighting synaptic remodeling as distinct mechanism in this model. Overall, this cross-species analysis clarifies the transcriptomic landscape of human MTLE and provides a framework for selecting appropriate epilepsy models.