Transcriptome profiling 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 epileptic seizures initiating in the hippocampus. mTLE can develop after exposure to risk factors such as seizure, trauma, and infection. Within the latent period between exposure and onset of recurrent seizures, pathological remodeling events occur which are believed to contribute to epileptogenesis. The molecular mechanisms responsible for epileptogenesis in the seizure network are currently unclear. We used the mouse intrahippocampal kainate model of mTLE to investigate transcriptional dysregulation in the ipsilateral-injected epileptogenic zone (EZ), and contralateral peri-ictal zone (PIZ) in the dentate gyrus (DG) of the hippocampus during the first 14-days after induction of status epilepticus (SE). DG were micro-dissected 3, 7 and 14-days after SE for high-throughput RNA-sequencing. In the EZ, dynamic transcriptional dysregulation was evident over 2-weeks with early expression of genes representing cell signaling, migration and proliferation. In the PIZ, gene dysregulation was most prominent at 3-days in similar domains. Inflammatory gene groups were also prominent over the 2-week epileptogenic period in the EZ and PIZ. We uncovered that the Wnt signaling pathway was dysregulated in the EZ and PIZ at 3-days and we validated these changes via immunohistochemistry. This suggests that critical gene changes occur early after neurological insult and that canonical Wnt signaling may play a role within this latent period. These findings offer new insights into gene expression changes that occur in the hippocampal DG early after SE and may help to identify novel therapeutic targets that could prevent epileptogenesis. Significance statementMesial temporal lobe epilepsy (mTLE) is a severe life-threatening condition that is often medically refractory. While risk factors for the delayed development of mTLE are well-known, there are currently no therapeutic interventions that prevent epileptogenesis. Knowledge of the gene dysregulation events that occur during the latent period between exposure and epilepsy is critical to understanding epileptogenesis and developing new therapies. We utilized a mouse model of adult focal mTLE, the most common form of adult clinical epilepsy, and investigated transcriptional changes in the dentate gyrus during the first 2-weeks after status epilepticus. These data provide new insights into specific gene changes and pathways within different regions of the seizure network that could be targeted to prevent the development of epilepsy.