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 () is alternatively spliced in its 3'-UTR, yielding two novel splice variants. These variants lack a ∼1.6 kb intron, which contains an microRNA-135 (miR135) target site. Unlike the human , the mouse lacks the splice donor/accepter sites. Thus, in the mouse , splicing was not detected. The two spliced mRNAs are extremely stable, are resistant to miR135-induced downregulation, and have greater translational output than the unspliced variant. Moreover, alternative 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, mRNA splicing was prevalent and region-specific. Unspliced was expressed more strongly in the hippocampus and midbrain versus the prefrontal cortex (PFC), and correlated with reduced levels of nSR100. Importantly, 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 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. Alternative splicing, which is prevalent in brain tissue, increases gene diversity. The serotonin-1A receptor gene () is a regulator of serotonin, which is implicated in mood and emotion. Here we show that human RNA is alternately spliced. Splicing removes a microRNA site to generate ultrastable RNA and increase expression. This splicing varies in different brain regions and is reduced in major depression. We also identify specific splice factors for RNA, showing they are also reduced in depression. Thus, we describe a novel mechanism to regulate gene expression through splicing. Altered levels of splice factors could contribute to depression by changing gene expression.