Transcriptome Profiling of the Hippocampal Seizure Network Implicates a Role for Wnt Signaling during Epileptogenesis in a Mouse Model of Temporal Lobe Epilepsy

Abstract

Mesial temporal lobe epilepsy (mTLE) is a life-threatening condition characterized by recurrent hippocampal seizures. mTLE can develop after exposure to risk factors such as febrile seizure, trauma, and infection. Within the latent period between exposure and onset of epilepsy, pathological remodeling events occur that contribute to epileptogenesis. The molecular mechanisms responsible are currently unclear. We used the mouse intrahippocampal kainite model of mTLE to investigate transcriptional dysregulation in the ipsilateral and contralateral dentate gyrus (DG), representing the epileptogenic zone (EZ) and peri-ictal zone (PIZ). DG were analyzed after 3, 7, and 14 days by RNA sequencing. In both the EZ and PIZ, transcriptional dysregulation was dynamic over the epileptogenic period with early expression of genes representing cell signaling, migration, and proliferation. Canonical Wnt signaling was upregulated in the EZ and PIZ at 3 days. Expression of inflammatory genes differed between the EZ and PIZ, with early expression after 3 days in the PIZ and delayed expression after 7–14 days in the EZ. This suggests that critical gene changes occur early in the hippocampal seizure network and that Wnt signaling may play a role within the latent epileptogenic period. These findings may help to identify novel therapeutic targets that could prevent epileptogenesis.