THE IMPACT OF EARLY ANTI-SEIZURE THERAPY ON DEVELOPMENTAL TRAJECTORIES AND COGNITIVE OUTCOMES IN ABSENCE SEIZURE MODELS

Absence seizures (ASs) are characterized by loss-of-consciousness accompanied by 2.5–4 Hz thalamocortical spike‑wave discharges (SWDs). Childhood absence epilepsy (CAE) is associated with neuropsychological comorbidities in ≈60% of patients, persisting despite seizure control. In the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), enhanced tonic GABAA-inhibition emerge by post‑natal day-17 (P17), preceding SWD maturation, and late cognitive comorbidities. It remains unanswered whether cognitive comorbidities relate to SWD maturation. We evaluated whether early administration of ethosuximide (ETX) or valproate (VPA) (300 mg/kg/day from P0), first-line ASs-drugs, mitigates developmental, SWDs and cognitive deficits. GAERS displayed accelerated sensorimotor milestones, early eye opening, and premature spatial learning before epileptiform activity. Recognition and working-memory impairments appeared after immature SWDs (P28), whereas spatial‑memory deficits emerged after mature SWDs (P40). Chronic ETX-treatment delayed eye opening (P12-15), improved working-memory, partially rescued long‑term spatial reference memory and recognition memory (P30,40,90) in GAERS but enhanced sensory maturation in non‑epileptic controls. However, seizure reduction does not fully predict cognitive rescue. VPA caused early recognition deficits in GAERS. Both drugs altered EEG first-harmonic frequency, changing thalamocortical-oscillation properties, which correlate with recognition memory performance. These findings suggest that GAERS' memory deficits follow epileptiform activity onset, implying cognitive dysfunction develops after immature SWDs. ETX ability to improve spatial working-, recognition and long-term spatial reference memory may be related to T-type calcium channel inhibition and SWDs attenuation, preserving cognitive neural-networks, although circuit-dependent. These results may guide the development of targeted therapeutic interventions for managing both seizure control and cognition in CAE.