In humans, neuroligin 3 (NLGN3) is a gene associated with autism, yet its role in behaviour and lifespan remains unclear. Loss of function of nlg3, the Drosophila melanogaster ortholog of human NLGN3, has been shown to disrupt social behaviours, suggesting its involvement in circuits underlying social interaction. To test which genetic pathways were influenced by nlg3, we analyzed RNA-seq data from Drosophila nlg3 loss of function mutants. We found that genes linked to longevity were downregulated, with gene ontology analysis indicating enrichment in aging-related pathways, including key regulators such as Drosophila FOXO (dFOXO) and heat shock proteins HSPs (stress-responsive chaperones linked to proteostasis). We manipulated nlg3 expression using deficiency lines, downregulation, and overexpression using the Gal4-UAS system. RT-qPCR revealed that overexpression of nlg3 significantly suppressed the expression of genes encoding HSP68 and HSP70; while the expression of dFOXO remained unchanged. In contrast, nlg3 reduction showed downregulation of the genes encoding dFOXO, HSP68, and HSP70. Behavioural assays showed that nlg3 overexpression increased social spacing and reduced lifespan, while partial loss of nlg3 in heterozygous deficiency flies extended lifespan without affecting social behaviour. Furthermore, RNAi-mediated knockdown led to an even stronger lifespan extension, but in that case, with increased social spacing. This supports a dosage-sensitive role for nlg3 in regulating social behaviour and lifespan in Drosophila, with implications for aging and neurodevelopmental disorders in more complex organisms.

1 Department of Biology, Faculty of Science, University of Western Ontario, London