{"paper_id":"076f44be-7277-40d4-9dff-dafcd703e1ff","body_text":"Abstract\nThe circuit mechanisms underlying focal epileptogenesis are, despite of decades of epilepsy research, still incompletely understood. In this study, we aimed to characterize the changes in hippocampal network activity induced by a potentially epileptogenic insult. In rats, long-lasting electrical perforant pathway stimulation leads in a high percentage of animals to the development of temporal lobe epilepsy. However, a subset of animals remains resilient against the stimulation. We monitored alterations of neuronal activity by chronically recording the local field potential (LFP) from the hippocampal dentate gyrus before, during and after the potentially epileptogenic insult. Intriguingly, epilepsy animals identified by subsequent spontaneous epileptic seizures were characterized by a transient increase in the aperiodic exponent suggesting a shift towards a reduced local excitation-to-inhibition (E/I) ratio during the first days after the perforant path stimulation. Furthermore, these animals developed a strong impairment of theta oscillation prevalence and regularity during early epileptogenesis. In contrast, resilient non-epilepsy animals without spontaneous seizures neither showed this modulation in E/I ratio nor a corruption of hippocampal theta activity. In fact, the increase in the aperiodic exponent on the first day after completion of the electrical stimulation paradigm could predict epileptogenesis with very high fidelity (AUC 0.92) and correlated significantly with later seizure rate. This finding opens the opportunity to dissect mechanisms of epileptogenesis and to test the effectiveness of anti-epileptogenesis treatment in very early disease stages by allowing identification of individuals at high risk. Furthermore, it might offer a potential explanation for the frequently observed failure of anti-epileptogenesis drugs boosting GABAergic inhibition.\nCompeting Interest Statement\nAS has received personal fees and grants from Angelini Pharma, Biocodex, Desitin Arzneimittel, Eisai, Jazz Pharmaceuticals, Takeda, UCB Pharma, and UNEEG Medical. NM has received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharmaceuticals, Fresenius Medical Care, Diamed, UCB Pharma, AngeliniPharma, BIAL and Sanofi-Aventis, has received royalties for consulting from UCB Pharma, Alexion Pharmaceuticals and Sanofi and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharmaceuticals, Novartis Pharma, and Sanofi. FR has received honoraria for lecturing and consultation from Angelini Pharma, Eisai GmbH, Jazz Pharma, Roche Pharma, Stoke Therapeutics, Takeda, and UCB Pharma, and has received financial research support from Dr. Schaer Deutschland GmbH, Vitaflo Deutschland GmbH, Nutricia Milupa GmbH, Desitin Pharma, Hamburg, Federal State of Hessen (via the LOEWE-Programme), Chaja Foundation Frankfurt, Reiss Foundation Frankfurt, Dr. Senckenbergische Foundation Frankfurt, Ernst Max von Grunelius Foundation Frankfurt, and Detlev-Wrobel Fonds for Epilepsy Research Frankfurt, outside the sub-mitted work. The remaining authors have no conflicts of interest.","source_license":"CC-BY-4.0","license_restricted":false}