S-011 ORAL | Astrocytes going wild: Understanding the epigenetic roots of epileptogenesis and epilepsy

Cellular and Molecular Neurobiology
Author: JOSE DANTE DANIEL GOMEZ CUAUTLE | Email: DANTEGCUAUTLE@GMAIL.COM

DANTE DANIEL GOMEZ CUAUTLE^1°, ALICIA ROSSI^1°, ALEJANDRO VILLAREAL^2°,  LUCIANA D´ALESSIO^3°, ALBERTO JAVIER RAMOS^1°

^1° LABORATORIO DE NEUROPATOLOGIA MOLECULAR – FACULTAD DE MEDICINA
^2° IBCN – FACULTAD DE MEDICINA
^3° LABORATORIO DE EPILEPSIA, CONDUCTA Y NEUROPATOLOGIA

Temporal lobe epilepsy (TLE) is the most prevalent epilepsy in humans. Retrospective studies in TLE patients show an initial precipitating event (IPE) in early childhood followed by a silent period, ultimately leading to chronic epilepsy. We hypothesized that epigenetics may be involved in epileptogenesis, particularly affecting astrocytes. To study this, we used the lithium-pilocarpine model of TLE in rats, primary astroglial cultures, and resected samples from TLE patients. We found that astrocytes from TLE patients showed reactive astrogliosis, increased DNA methylation, and downregulation of homeostatic genes Kir4.1, Glutamine Synthetase and AQP4 by immunohistochemistry. In Wistar rats, the IPE induced by lithium-pilocarpine treatment (30 mg/kg IP) caused hypermethylation of astrocytes at 7, 21, and 35 days post-IPE, indicating persistent epigenetic alterations. Additionally, we observed the downregulation of homeostatic astroglial genes AQP4, glutamine synthase (GS), and Kir4.1, along with an increased proinflammatory response (C3, MAFG) and elevated DNMT expression by qPCR. These alterations were mimicked in primary astrocyte cultures exposed to DAMP HMGB1 (500 ng/ml; 18 hours) and PAMP LPS (25 ng/ml; 18 hours) and were reversed by the DNMT inhibitor decitabine (100µM). These findings show that astrocytes are pathologically altered, potentially sustaining the long-term changes underlying epilepsy. Grants PICT 2021-0760/2019-0851; UBACYT, PIP Conicet.