Duplications of chromosomal region 15q11.2-q13.1 cause Duplication 15q (Dup15q) syndrome, characterized by a high incidence of autism spectrum disorder (ASD), seizures, and cognitive impairment. This duplication includes the UBE3A gene, and elevated levels of UBE3A in neurons are thought to be the primary cause of Dup15q syndrome. UBE3A overexpression in other cell types has been largely unexplored. Evidence from mouse models indicates that UBE3A is bi-allelically expressed in glial cells and maternally expressed in neurons. Duplications of the UBE3A locus should cause elevated UBE3A in glia as well as neurons. Here we elevated the fly homolog (Dube3a) in glial cells and evaluated Dup15q related phenotypes. We found that elevated Dube3a levels in glia results in a robust seizure susceptibility phenotype absent in animals overexpressing Dube3a in neurons. To identify changes in gene expression, we performed RNAseq and identified 497 differentially expressed transcripts in elav>Dube3a animals (neuronal expression) and 1,222 differentially expressed transcripts in Repo>Dube3a animals (glial expression). 854 transcripts were differentially expressed in glia compared to neurons and showed significant enrichment in synaptic transmission, substrate specific channels, and neurotransmitter synthesis. Transcript expression of the presynaptic active zone protein bruchpilot was reduced by 2-fold in glial versus neuronal overexpression of Dube3a, and a similar reduction was observed at the protein level. Interestingly we saw no change in the neuronal marker elav in the brain, indicating that the reduced expression of presynaptic proteins is not due to a loss of neurons. Furthermore, a reduction of on/off transients was observed in electroretinograms of flies overexpressing Dube3a in glia, indicating impaired synaptic transmission. These results demonstrate that elevated levels of Dube3a in glial cells drive changes in key neuronal functions that may underlie Dup15q seizure phenotypes. We observe a similar seizure susceptibility phenotype when human UBE3A is overexpressed in fly glial cells, potentially indicating a conserved mechanism between fly and human UBE3A in seizure production. Currently we are working to identify the causal genes mis-regulated in glia and the nature of impairment between glia and neurons that result in seizure susceptibility due to glial Dube3a overexpression. These studies may lead to the identification of new genes and pathways for novel epilepsy treatments in Dup15q syndrome..