Neural APLNR Deficiency-Induced Anxiety-Like Behaviors Associate with the Alteration of Global Gene Expression

Anxiety disorders are one of the most common mental disorders. Dysregulation of apelinergic system, comprising apelin receptor (APLNR) and its two ligands, apelin (APLN) and elabela, may contribute to the pathogenesis of anxiety disorders. However, the exact role of APLNR in anxiety and underlying mechanisms remain elusive. To avoid embryonic or preweaning lethality of complete Aplnr knockout, we generated neural cell-specific Aplnr knockout mice (Aplnr-cKO^nestin). The Aplnr-cKO^nestin mice exhibit anxiety-like behaviors by elevated plus-maze test and marble burying test. To investigate the underlying mechanisms, transcriptomic profiling and validation were performed in the prefrontal cortex (PFC) and amygdala. 897 genes and 473 genes were significantly dysregulated in the PFC and amygdala of Aplnr-cKO^nestin mice (p < 0.05), respectively, while 20 genes and 1 gene were retained in the PFC and amygdala (adjusted p < 0.05), respectively. The dysregulated genes were involved in a number of pathways including inflammatory response, immune response, oxytocin signaling pathways etc. Furthermore, key hub genes in inflammatory and oxytocin signaling pathway were identified by network analysis. In this study, we demonstrated that neural cell-specific APLNR deficiency contributes to anxiety-like behaviors in mice, which is associated with the alteration of global gene expression, highlighting APLNR as a potential therapeutic target for anxiety disorder treatment.