Wnt activation during epileptogenesis prevents pathological immature dentate granule cell morphological changes in...

Temporal lobe epilepsy (TLE) most commonly presents clinically with unilateral or bilateral hippocampal seizure onsets. Antiseizure medications are often ineffective, and epilepsy surgery outcomes are variable. TLE often occurs after exposure to risk factors; this latent period provides the opportunity for preventative treatments, however, there are currently no clinically approved anti-epileptogenic therapies. In this study, we investigate the role of Wnt signaling in dentate granule cell remodeling during epileptogenesis using two mouse TLE models, the intrahippocampal kainate model of unilateral TLE (IHK), and the intraperitoneal kainate model of bilateral TLE (IPK). We examined histological changes in adult-born immature dentate granule cells as these cells have been heavily implicated in the pathogenesis of TLE, and clinical TLE is typically initiated in adulthood. We observed that adult-born immature dentate granule cells undergo pathological morphological changes during epileptogenesis in both the IHK and IPK models of TLE. These changes differed between the two models and by laterality in IHK. Wnt signaling also decreased in immature dentate granule cells specifically in the epileptogenic zones in both models. When mice were treated with SB415286, a highly selective Wnt activator, Wnt signaling in immature dentate granule cells was restored to baseline levels and pathological granule cell morphological changes were reduced in both models. These data suggest that a reduction in Wnt signaling in immature dentate granule cells plays an etiological role in epileptogenesis, and that restoring Wnt signaling using Wnt activating drugs or alternative agents may have therapeutic potential as an anti-epileptogenic strategy in TLE.