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

Abstract

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 (FeCl3) post-traumatic epilepsy (PTE) and lithium-pilocarpine-induced (LiCl-Pilo) status epilepticus (SE). By integrating Electrophysiology (EEG), {gamma}-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. 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.