Tissue oxygenation dynamics during transition from seizure to spreading depolarization in rat brain

Objective: Spreading depolarization (SD) is a phenomenon underlying various neurological conditions, including epilepsy. Researchers have suspected that local tissue oxygenation breakdown induces spontaneous SD. In this study, we investigated the relationship between spontaneous epileptic seizures and SD, with a focus on the role of local tissue oxygenation during the transition from seizure to seizure-associated SD. Methods: We applied a long pulse voltametric method to characterize local tissue oxygenation and extracellular space (ECS) volume change in the hippocampus (HC) of freely moving epileptic rats (six males and three females). Recordings were performed during the normal state of vigilance, spontaneous seizures, seizure-associated SD events, and their transitions. Results: No significant breakdown in local tissue oxygenation of HC was detected before the SD onset during the seizure to SD transition. In contrast, decreased ECS volume in the HC was observed before SD onset during this transition. Significance: Using a novel electrochemical approach in freely behaving rats with intact cerebral autoregulation, we demonstrate that there is no significant breakdown of local tissue oxygenation during seizure to SD transition. However, the ECS begins to shrink during seizure, before SD onset, suggesting that ECS shrinkage may play a leading role in this transition. These findings refine our understanding of the mechanisms driving seizure-associated SD and suggest that ECS may represent a potential therapeutic target in epilepsy and SD-associated neurological disorders.