Abstract
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 volume in the hippocampus (HC) of freely moving epileptic rats (male 6, female 3). Recordings were performed during the normal state of vigilance, spontaneous seizures, and seizure-associated SD events, as well as during their transitions. RESULTS: No significant breakdown in local tissue oxygenation of HC was detected before SD onset during the seizure to SD transition. In contrast, a 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 ECS shrinkage, rather than breakdown of local tissue oxygenation, plays a leading role in SD initiation during seizure to SD transition. These findings refine our understanding of the mechanisms driving seizure-associated SD and suggest that ECS dynamics may represent an important therapeutic target in epilepsy and other SD-associated neurological disorders.