LINE-1 Retrotransposon Activation and 5-Gene Dysregulation as a Common Pathological Signature in Post-Traumatic and Status Epilepticus Models of Epilepsy

The transition from an initial brain insult to chronic epilepsy remains a critical challenge in clinical neuroscience, often involving complex molecular shifts that are difficult to capture through single-gene analysis. This study investigated the existence of a convergent pathway of genomic instability across two distinct etiological models: iron-induced (FeCl ₃ ) post-traumatic epilepsy (PTE) and lithium-pilocarpine-induced (LiCl-Pilo) status epilepticus (SE). By integrating Electrophysiology (EEG), γ-oscillation spectral analysis, multi-unit activity (MUA) recordings with behavioural assessments Morris Water Maze (MWM) and Open Field Test (OFT) we validated and established the chronic hyperexcitability and associated cognitive-emotional co-morbidities of these two models. Which further served as a functional backdrop for investigating a targeted 8-gene panel consisting of GABRA2, KCNN2, KCNAB1, GRIK1, BCL11A, BRD7, STX1B , and PNPO . RT-PCR analysis demonstrated a systemic dysregulation of 5 genes out of these 8 genes, mirroring the simultaneous collapse of inhibitory signalling, membrane stability, and neurotransmitter metabolism seen in human phenotypes. Crucially, our findings reveal a relationship between suppressed FOXO3 expression and the robust activation of LINE-1 (L1) retrotransposons (ORF1/ORF2). Suggesting that oxidative stress may create a permissive landscape for L1-mediated genomic instability, potentially entrenching the disease state. While the clinical roles of these genes are well documented, our study demonstrates that these rat models provide a high-fidelity platform for complex multigene studies and gene-level therapeutic exploration. Furthermore, in-silico docking identified Fisetin as a high-affinity ligand for the dysregulated proteins, offering a promising multi-target strategy for stabilizing the epileptic genome.