A Novel Alternative Splicing Mechanism That Enhances Human 5-HT1A Receptor RNA Stability Is Altered in Major Depression

The serotonin-1A (5-HT1A) receptor is a key regulator of serotonergic activity and is implicated in mood and emotion. However, its post-transcriptional regulation has never been studied in humans. In the present study, we show that the "intronless" human 5-HT1A gene (HTR1A) is alternatively spliced in its 3'-UTR, yielding two novel splice variants. These variants lack a similar to 1.6 kb intron, which contains an microRNA-135 (miR135) target site. Unlike the human HTR1A, the mouse HTR1A lacks the splice donor/accepter sites. Thus, in the mouse HTR1A, splicing was not detected. The two spliced mRNAs are extremely stable, are resistant to miR135-induced down-regulation, and have greater translational output than the unspliced variant. Moreover, alternative HTR1A RNA splicing is oppositely regulated by the splice factors PTBP1 and nSR100, which inhibit or enhance its splicing, respectively. In postmortem human brain tissue from both sexes, HTR1A mRNA splicing was prevalent and region-specific. Unspliced HTR1A was expressed more strongly in the hippocampus and midbrain versus the prefrontal cortex (PFC), and correlated with reduced levels of nSR100. Importantly, HTR1A RNA splicing and nSR100 levels were reduced in the PFC of individuals with major depression compared with controls. Our unexpected findings uncover a novel mechanism to regulate HTR1A gene expression through alternative splicing of microRNA sites. Altered levels of splice factors could contribute to changes in regional and depression-related gene expression through alternative splicing.