Impact of Larval Sertraline Exposure on Alternative Splicing in Neural Tissue of Adult Drosophila melanogaster

Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commonly used to treat various psychiatric disorders such as depression and anxiety due to its ability to increase serotonin availability in the brain. Recent findings suggest that sertraline may also influence the expression of genes related to synaptic plasticity and neuronal signaling pathways. Alternative splicing, a process that allows a single gene to produce multiple protein isoforms, plays a crucial role in the regulation of neuronal functions and plasticity. Dysregulation of alternative splicing events has been linked to various neurodevelopmental and neurodegenerative diseases. This study aims to explore the effects of sertraline on alternative splicing events, including exon inclusion, exon exclusion, and mutually exclusive splicing events, in genes associated with neuronal function in <i>Drosophila melanogaster</i> and to use this model to investigate the molecular impacts of SSRIs on gene regulation in the nervous system. RNA sequencing (RNA-seq) was performed on central nervous system samples from <i>Drosophila melanogaster</i> adults exposed to sertraline for 24 h when they were third instar larvae. Alternative splicing events were analyzed to identify changes in exon inclusion and exclusion, as well as intron retention. Sertraline treatment significantly altered alternative splicing patterns in key genes related to neuronal stability and function. Specifically, sertraline promoted the inclusion of long <i>Ank2</i> isoforms, suggesting enhanced axonal stability, and favored long <i>ATPalpha</i> isoforms, which support Na⁺/K⁺ ATPase activity essential for ionic balance and neuronal excitability. Intron retention in the <i>yuri</i> gene suggests that cytoskeletal reorganization could impact neuronal morphology. Additionally, splicing alterations in <i>sxc</i> and <i>Atg18a</i> indicate a potential influence of sertraline on epigenetic regulation and autophagy processes, fundamental aspects for neuronal plasticity and cellular homeostasis. These findings suggest that sertraline influences alternative splicing in the central nervous system of <i>Drosophila melanogaster</i>, potentially contributing to its therapeutic effects by modulating neuronal stability and adaptability.