Introduction: Epilepsy occurs frequently after cortical injury (e.g. TBI). While anti-epileptic medications can prevent early seizures, there are currently no treatments for delayed-onset epilepsy. Therapies targeting neuronal-network remodeling may prevent delayed epilepsy in high-risk patients. Mouse epilepsy models recapitulate aspects of human epilepsy, specifically spontaneous recurrent seizures and neuronal-network remodeling. We demonstrate that the Wnt pathway is dysregulated in the ictal and peri-ictal zones in a mouse model of temporal lobe epilepsy, and that a novel Wnt antagonist compound modulates neuronal-network remodeling in the hippocampus.
Methods: Seizures were induced by intrahippocampal kainate injection and compared with saline-injected controls in 3-4-month-old transgenic mice, in which adult-born dentate granule cells express GFP for 2-weeks after mitosis. Animals also received BRDU 48h-72h after seizure induction. Tissue was analyzed using immunohistochemistry and confocal microscopy, and transcriptome analysis was performed using RNA extracted from anatomically microdissected dentate gyrus.
Results: Our results demonstrate that hippocampal neurogenesis and dendritic arborization are increased in the peri-ictal regions, and decreased in the ictal zone 2-weeks after injection. Our preliminary qPCR data suggest canonical Wnt pathway dysregulation in the hippocampus immediately after seizure induction. We are using systemic administration of XAV939, a canonical Wnt antagonist, to confirm the Wnt pathway’s role in neurogenesis and neuronal network formation. Preliminary data demonstrate increased neurogenesis in the peri-ictal regions of mice treated with this Wnt antagonist, a potentially protective adaptive reflex in epilepsy.
Conclusions: Ictal and peri-ictal zone remodeling is critical in the development and maintenance of epilepsy. Our studies aim to understand the differences in neuronal network remodeling and the transcriptional changes responsible between these regions. We hypothesize the Wnt pathway is critical to changes induced by ictal activity and are utilizing small molecule modulation of Wnt activity to investigate this pathway as a putative target to prevent the development of epileptic circuits in peri-ictal regions.
Patient Care: Research into fundamental mechanisms that cause the development of epilepsy and the effect of novel compounds on these processes can lead to novel therapies that prevent the development of epilepsy in high risk patients (e.g. post-TBI)
Learning Objectives: 1. Epilepsy is characterized by rewiring of neuronal networks that causes neuronal hyper-excitability
2. Changes in neuronal connectivity differ in the ictal and peri-ictal zones. Molecular and structural processes that underlie these changes represent potential therapeutic targets in the development of epilepsy
3. The small molecule Wnt antagonist XAV939 modulates the neuronal network in peri-ictal regions by increasing neurogenesis and dendrite arborization in the hippocampus