Project Summary/Abstract Epilepsy is a common and disabling disease for which current treatments remain inadequate. Epilepsy is known to have a major genetic contribution, but a small proportion of epilepsy overall is explained by known genes and mechanisms. Thus, there is a critical need to identify the molecules and pathways that underlie epilepsy pathophysiology and to find novel therapeutic strategies. Focusing on pathways which lead to epilepsy-related phenotypes in diverse species and model systems may help accelerate the discovery process. Recently we found mutations in the Prickle genes can contribute to seizures in multiple species ranging from flies to humans. This system can provide a basis for the development of safer and more effective drug regimens for treating epilepsy. Our preliminary findings led us to the hypothesis that mutations in the PRICKLE pathway are associated with epilepsy and that Prickle-modulating reagents can be used to treat epilepsy or seizures. The objective of this R01 application is to identify the molecules involved in Prickle signaling and to determine whether Prickle pathway-modulating reagents alleviate seizures in our multiple model systems. The studies proposed here should both further our understanding of the biology of the Prickles and their connection to epilepsy, and lead to new therapeutic modalities. Our specific aims are: to 1) Test Prickle-pathway molecules as anti-epilepsy drug targets and 2) Test Wnt5a and related molecules as anti-epileptics in Prickle mutant mice. These experiments should provide insight into the biology of Prickle signaling, how it and whether Prickle-modulating reagents offer new epilepsy treatments.