952C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
Walt Krueger ^1,2; Bidisha Roy ¹; Jungsoo Han ³; Benjamin Geier ^1,2; Lawrence Reiter ^1,4,5

Affiliations:
1) Department of Neurology, UTHSC, Memphis, TN; 2) IBSP Program, UTHSC, Memphis, TN; 3) Department of Biochemistry, UT Southwestern, Dallas, TX; 4) Department of Pediatrics, UTHSC, Memphis, TN; 5) Department of Anatomy and Neurobiology, UTHSC, Memphis, TN

Keywords:
b. neural disorder; f. drug discovery

Duplication 15q syndrome (Dup15q) is caused by the presence of at least one extra copy of the 15q11.2-q13.1 region. Characteristics of Dup15q include hypotonia, intellectual disability, autism spectrum disorder and, in the majority of isodicentric 15 cases, pharmacoresistant epilepsy. We previously constructed a fly model that successfully recapitulates the seizure phenotype observed in Dup15q individuals by overexpressing Drosophila Ube3a (Dube3a) in glial cells. To identify new anti-epileptic drugs, our lab developed a medium throughput screening method to repurpose previously FDA or otherwise approved chemical libraries for their ability to suppress seizures. We recently used this model to screen 1,280 compounds from the Prestwick Chemical Library. Eight compounds were identified that reduce seizure recovery time by at least 50% in both male and female flies. Most of these compounds act through serotonin or dopamine receptors to increase Na⁺/K⁺-ATPase activity in glial cells (Roy et al. (2020) Biol Psychiatry 88(9):698-709). In the current study, we evaluated 70 compounds from the Screen-Well Ion Channel Ligand Library for their ability to suppress seizures in our glial cell specific epilepsy model. The primary screen was composed of 24 calcium channel modulators, 23 potassium channel modulators, 10 sodium channel modulators, 7 intracellular calcium modulators, and 6 other miscellaneous drugs. We identified 8 compounds that suppress seizures in repo>Dube3a flies by at least 50%. Seventy-five percent of these compounds are potassium modulators and 25% are calcium modulators. ATP-sensitive Inward Rectifying K+ channel (KATP) modulation is a shared commonality among 3 of the 8 compounds. To evaluate the potentially critical role KATP modulation plays in seizure suppression, as well as to investigate the importance of glial-specific neuronal modulation, we are currently testing drug efficacy on flies that simultaneously express Dube3a and an RNAi against the Drosophila homologue for KATP (Irk) in glial cells. We expect to find that KATP modulators fail to suppress seizures in the absence of sufficient irk channel expressions. These studies will lead directly to new candidate drugs, specific ion channel agonists and antagonists, that may eventually be used clinically to suppress seizures in Dup15q syndrome.