Long-term consequences of a prolonged febrile seizure in a dual pathology model

Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits.

Research highlights
► We have developed a two-hit animal model of temporal lobe epilepsy following prolonged febrile seizures which leads to spontaneous recurrent seizures (SRS) of limbic origin in all animals after a 2-month latent period.
► The most important finding in this manuscript is that hippocampal injury precedes spontaneous recurrent seizures.
► We demonstrated that prior to SRS onset hippocampal atrophy is secondary to a lateralized mild neuronal loss and a significant decrease in spine density.
► Finally, we observed at P80 an increased level of NR2A expression which could contribute to the cognitive changes in our model.