ASTROCYTE-DRIVEN HYPEREXCITABILITY AS A THERAPEUTIC TARGET IN EPILEPSY

Epilepsy affects about 50 million people worldwide, and despite advances in antiseizure therapies, nearly one-third of patients experience refractory seizures. The associated morbidity and mortality underscore the urgent need for novel treatment strategies. This project investigates astrocyte hyperexcitability as an emerging target in epilepsy. We will delineate mechanisms by which astrocytes contribute to epileptogenesis and ictogenesis, with a focus on intracellular signaling and gliotransmitter release. Prior work suggests that ictal calcium elevations in astrocytes precede neuronal activation, potentially triggering the release of gliotransmitters that initiate and propagate epileptic activity. To interrogate astrocyte–neuron interactions in vivo, we employ a combination of electrophysiology, two-photon laser scanning microscopy, and optogenetics in mouse models of epilepsy. In parallel, we examine the interplay between epilepsy and spreading depolarization (SD), a phylogenetically conserved electrophysiological phenomenon characterized by profound cellular depolarization and subsequent suppression of activity, often accompanied by hyperpolarization. SD is implicated in migraine aura and plays a central role in traumatic brain injury and stroke, yet its physiological function remains incompletely understood. We hypothesize that SD may contribute to seizure termination. By optogenetically inducing SD, we aim to elucidate its dynamics in epileptic networks and assess its therapeutic potential. Collectively, these studies seek to clarify astrocyte-driven mechanisms of network hyperexcitability and evaluate SD-based interventions, with the goal of advancing innovative treatments for epilepsy and informing therapeutic approaches for other neurological disorders in which SD is a key process.