NEUROPROTECTIVE POTENTIAL OF PAROXYSMAL DEPOLARIZATION SHIFTS

Epilepsy lacks disease-modifying treatments, as current antiseizure medications only provide symptomatic relief and often fail to produce full seizure control. These limitations arise partly from an incomplete understanding of epileptogenesis, the process through which neural circuits undergo lasting pathophysiological changes that increase vulnerability to spontaneous seizure recurrence. Evidence from animal models shows that abnormal electrical activity precedes chronic seizures and appears on EEG as interictal spikes, which originate from synchronized neuronal discharges known as paroxysmal depolarization shifts (PDS). Understanding the role of PDS in epileptogenesis may therefore guide future therapeutic approaches. Using an in vitro model that induces epileptiform PDS, we reproduced key features of epilepsy, including neuronal hypersynchrony, seizure-like events, and altered metabolism (Kubista et al., 2025, JNeurosci, 45(21)). This system enables mechanistic studies on an accelerated timescale. Our data suggest a dual role for PDS in epileptogenesis. Although prolonged PDS activity contributes to seizure development, transient PDS episodes can exert neuroprotective effects. Imaging and patch-clamp measurements in primary hippocampal cocultures revealed that 24 hours of recurrent PDS firing triggered neuronal glutaminolysis and decreased excitability. These neurons were consequently less susceptible to seizures in the 0-Mg²⁺ acute seizure model. Moreover, neuronal viability assays demonstrated that PDS exposure reduced excitotoxic damage. In summary, while sustained PDS activity promotes seizure formation, short-term PDS firing temporarily dampens excitability and protects neurons. These findings suggest that precisely timed modulation of PDS could prevent epileptogenesis after an initial insult, whereas premature suppression might worsen neuronal damage.
Support: FWF [Project PAT8605623]; GFF NÖ [LSC19-017, FTI24-D-026].