Glial expression ofDrosophila UBE3Acauses spontaneous seizures modulated by 5-HT signaling

Abstract

AbstractMisexpression of the E3 ubiquitin ligaseUBE3Ais thought to contribute to a range of neurological disorders. In the context of Dup15q syndrome, excess genomic copies ofUBE3Ais thought to contribute to the autism, muscle tone and spontaneous seizures characteristic of the disorder. In aDrosophilamodel of Dup 15q syndrome, it was recently shown glial-driven expression of theUBE3Aorthologdube3aled to a “bang-sensitive” phenotype, where mechanical shock triggers convulsions, suggesting glialdube3aexpression contributes to hyperexcitability in flies. Here we directly compare the consequences of glial- and neuronal-drivendube3aexpression on motor coordination and neuronal excitability in Drosophila. We utilized IowaFLI tracker and developed a hidden Markov Model to classify seizure-related immobilization. Both glial and neuronal drivendube3aexpression led to clear motor phenotypes. However, only glial-drivendube3aexpression displayed spontaneous immobilization events, that were exacerbated at high-temperature (38 °C). Using a tethered fly preparation we monitored flight muscle activity, we found glial-drivendube3aflies display spontaneous spike discharges which were bilaterally synchronized indicative of seizure activity. Neither control flies, nor neuronal-dube3aoverexpressing flies display such firing patterns. Prior drug screen indicated bang-sensitivity in glial-drivendube3aexpressing flies could be suppressed by certain 5-HT modulators. Consistent with this report, we found glial-drivendube3aflies fed the serotonin reuptake inhibitor vortioxetine and the 5HT2Aantagonist ketanserin displayed reduced immobilization and spike bursting. Together these findings highlight the potential for glial pathophysiology to drive Dup15q syndrome-related seizure activity.