Glial expression of Drosophila UBE3A causes spontaneous seizures that can be modulated by 5-HT signaling

Misexpression of the E3 ubiquitin ligase gene UBE3A is thought to contribute to a range of neurological disorders. In the context of Dup15q syndrome, additional genomic copies of UBE3A give rise to the autism, muscle hypotonia and spontaneous seizures characteristics of the disorder. In a Drosophila model of Dup 15q syndrome, it was recently shown that glial-driven expression of the UBE3A ortholog dube3a led to a "bang-sensitive" phenotype, where mechanical shock triggers convulsions, suggesting glial dube3a expression contributes to hyperexcitability in flies. Here we directly compare the consequences of glial- and neuronal-driven dube3a expression on motor coordination and seizure susceptibility in Drosophila. To quantify seizure-related behavioral events, we developed and trained a hidden Markov model that identified these events based on automated video tracking of fly locomotion. Both glial and neuronal driven dube3a expression led to clear motor phenotypes. However, only glial-driven dube3a expression displayed spontaneous seizure-associated immobilization events, that were clearly observed at high-temperature (38 °C). Using a tethered fly preparation amenable to electrophysiological monitoring of seizure activity, we found glial-driven dube3a flies display aberrant spontaneous spike discharges which are bilaterally synchronized. Neither neuronal-dube3a overexpressing flies, nor control flies displayed these firing patterns. We previously performed a drug screen for FDA approved compounds that can suppress bang-sensitivity in glial-driven dube3a expressing flies and identified certain 5-HT modulators as strong seizure suppressors. Here we found glial-driven dube3a flies fed the serotonin reuptake inhibitor vortioxetine and the 5-HT_2A antagonist ketanserin displayed reduced immobilization and spike bursting, consistent with the previous study. Together these findings highlight the potential for glial pathophysiology to drive Dup15q syndrome-related seizure activity.