Cognitive impairment in the WAG/Rij rat absence model is secondary to absence seizures and depressive-like behavior

Neuropsychiatric comorbidities are common in patients with epilepsy, remaining still an urgent unmet clinical need. Therefore, the management of epileptic disorders should not only be restricted to the achievement of seizure-freedom but must also be able to counteract its related comorbidities. Experimental animal models of epilepsy represent a valid tool not only to study epilepsy but also its associated comorbidities. The WAG/Rij rat is a well-established genetically-based model of absence epilepsy with depressive-like comorbidity, in which learning and memory impairment was also recently reported. Aim of this study was to clarify whether this cognitive decline is secondary or not to absence seizures and/or depressive-like behavior. The behavioral performance of untreated and ethosuximide-treated (300 mg/kg/day; 17 days) WAG/Rij rats at 6 and 12 months of age were assessed in several tests: forced swimming test, objects recognition test, social recognition test, Morris water maze and passive avoidance. According to our results, it seems that cognitive impairment in this strain, similarly to depressive-like behavior, is secondary to the occurrence of absence seizures, which might be necessary for the expression of cognitive impairment. Furthermore, our results suggest an age-dependent impairment of cognitive performance in WAG/Rij rats, which could be linked to the age-dependent increase of spike wave discharges. Consistently, it is possible that absence seizures, depressive-like behavior and cognitive deficit may arise independently and separately in lifetime from the same underlying network disease, as previously suggested for the behavioral features associated with other epileptic syndromes.