Blocking ATP signaling and ROS generation preserves neurogenesis and network activity In epileptogenesis In hippocampal organotypic slice cultures.

Abstract

Epilepsy is a common neurological disorder, which lacks a comprehensive understanding of epileptogenesis. Temporal lobe epilepsy (TLE) in particular, often involves the hippocampus, with gliosis and abnormal neurogenesis. In our study, we aimed to evaluate and mitigate abnormal neurogenesis in TLE using an ex vivo model of hyperexcitable hippocampal organotypic culture slices (hOTCs) with disrupted GABAergic transmission by picrotoxin (PTX). Here, we observed that the epileptiform environment in hOTCs reduced newborn neuron density and impaired dendritic growth. Additionally, inhibiting newborn neurons restored normal firing patterns, indicating a link between neurogenesis and network activity. When we therefore targeted neuroinflammation in epileptogenesis through ATP signaling pathways by blocking purinergic receptors (P2XRs) or by reducing oxidative stress with cerium oxide nanoparticles, we observed recovery in most of the features studied. However, recovery in dendritic arborization occurred with P2XR inhibition but not in oxidative stress reduction. As a general conclusion, we observed that modulating ATP signaling prevented epileptiform activity, showcasing the importance of ATP and ROS in neurogenesis.