An unbiased drug screen for seizure suppressors in Dup15q syndrome reveals 5HT1A and dopamine pathway activation as potential therapies

Abstract

Duplication 15q syndrome (Dup15q) is a rare neurogenetic disorder characterized by autistic features and difficult to control (pharmacoresistant) epileptic seizures. Most individuals with isodicentric (idic15) have been on multiple medications to control their seizures and some are still seizing after years of treatment. We recently developed a model of Dup15q in Drosophila by elevating levels of fly Dube3a in glial cells, not neurons. Unlike other Dup15q models, these flies develop seizures that worsen as flies age. Here we used this new model to screen for previously approved compounds from the Prestwick Chemical Library which are able to suppress seizures in flies over-expressing Dube3a in glia using the pan glial driver repo-GAL4. We identified 17 out of 1280 compounds in the library that could suppress a bang sensitive (seizure) phenotype. Eight of these compounds were able to suppress seizures significantly in both males and females by at least 50%. Half of these strong seizure suppressors regulated either serotoninergic or dopaminergic signaling and subsequent experiments confirmed that seizure suppression occurs through stimulation of serotonin receptor 5-HT1A but can be further suppressed with the addition of L-Dopa (Levodopa). We provide further support for a seizure model where Dube3a regulation of the Na+/K+ exchanger ATP in glia can also be modulated by serotonin/dopamine signaling. Finally, based on these pharmacological and genetic studies, we present an argument for the use of 5-HT1A agonists in the treatment of Dup15q epilepsy.