Larval exposure to sertraline induces dose- and time-dependent remodeling of neuronal alternative splicing in adult Drosophila melanogaster

BACKGROUND: Alternative splicing is a central procedure that increases the variety of the transcriptome and helps regulate several neuronal processes. Various pharmacological factors have the capacity to alter splicing patterns, which could potentially affect cellular function. Sertraline, a selective serotonin reuptake inhibitor widely used in the treatment of neuropsychiatric disorders, also regulates intracellular pathways linked with calcium signaling and other cellular processes. However, information about its potential impact on the post-transcriptional regulation of the transcriptome is still insufficient. METHODS AND RESULTS: In this study, we analyzed whether exposure to sertraline changes alternative splicing patterns in the neural transcriptome of Drosophila melanogaster. Third-instar larvae were exposed to two concentrations of the drug during different periods of time, and the RNA obtained from adult heads was analyzed by RNA sequencing (RNA-seq). The evaluation of differential splicing revealed modifications that depend on the experimental condition in exon usage, including exon skipping, intron retention, and alternative splice-site selection. The affected genes showed functional enrichment in processes related to ion transport, synaptic organization, and neuronal signaling. The in silico reconstruction and translation of representative isoforms indicated possible modifications in protein architecture, including predicted loss of domains or truncations. CONCLUSIONS: Taken together, these results indicate that sertraline can remodel alternative splicing in the neuronal transcriptome in a manner dependent on dose and exposure time. These findings suggest a possible additional mechanism through which larval sertraline exposure could influence neuronal function via persistent remodeling of RNA processing in adult neural tissue, as inferred from RNA-seq-based transcriptomic analyses.