Abstracts

Rationale: Dentate granule neurons are born throughout adulthood and are important for hippocampal functioning. Status epilepticus (SE) enhances neurogenesis, but migration is abnormal and aberrant connections are formed, which may underlie emergence of recurrent seizures and cognitive impairment. Stress is a powerful modulator of neurogenesis and is also the most important self-reported trigger for seizures. Activation of the HPA-axis results in high levels of corticosteroids that can bind to the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Previously our lab has shown that the GR controls the correct integration of the newborn neurons in the hippocampus. This lead us to the hypothesis that activation of the GR might be involved in aberrant integration of newborn cells after SE. Using a pharmacological approach, we have investigated the function of the GR in this process.Methods: Male C57BL/6J mice were pre-treated with corticosterone (GR agonist) or RU486 (GR antagonist) 30 minutes before treatment with kainate (KA). Repeated doses KA were administered until SE occurred. Newborn neurons were identified by the expression of doublecortin (DCX). One group of animals was sacrificed 3 days after SE for immunochemistry to characterize changes in neurogenesis. Spatial memory was tested 5 weeks after SE in a parallel group when the newborn neurons are supposed to be matured and fully integrated into the existing network.Results: Three days after SE, we showed an increase of DCX positive cells, but if the GR was activated, this increase was prevented. We observed a similar finding for dendritic complexity of newborn cells where corticosterone reduced the seizure-induced increase in dendritic arborization. GR blockage did not change dendritic complexity compared to kainate treatment. In our behavioral studies we did not observe a change in the learning curve, but we found a change in learning strategy after KA administration that was exaggerated by corticosterone administration, but remained unchanged after RU486 pre-treatment compared to kainate treated animals. Conclusions: Together, our data suggest that the GR is involved in seizure-induced aberrant integration of adult born neurons with consequences for hippocampal learning strategies, in interaction with, perhaps, the mineralocorticoid receptor.