Small molecule ion channel agonist/antagonist screen reveals seizure suppression via glial Irk2 activation in a Drosophila model of Dup15q syndrome

The neurogenetic disorder duplication 15q syndrome (Dup15q) is characterized by a high incidence of autism spectrum disorder (ASD) and pharmacoresistant epilepsy. Standard-of-care broad-spectrum anti-seizure medications (ASM) often fail to control seizures in Dup15q, emphasizing the need for the identification of new therapeutic compounds. Previously, we generated a model of Dup15q in Drosophila melanogaster by overexpressing Dube3a in glial cells, instead of neurons. This model recapitulates the spontaneous seizures present in Dup15q patients. Here, we screened a set of FDA-approved compounds for their ability to suppress seizures in repo > Dube3a flies. We used 72 compounds from the Enzo SCREEN-WELL Ion Channel Library for primary screening of seizure suppression. Six compounds were identified that significantly reduced seizure duration. Furthermore, the compounds that passed the primary and secondary screenings were associated with K⁺ channels. Glial-specific knockdown of the inward rectifying potassium (Irk) 2 channel exacerbated the seizure phenotype in these animals indicating a mechanism of action for drugs that bind irk2, like minoxidil, and can suppress seizures through the rebalancing of K⁺ extracellularly. This pharmacological and molecular investigation further supports the role of extracellular K⁺ content in Dup15q seizure activation and provides a putative target for therapeutic intervention.