Overexpression of Hspa1b in the mouse hippocampus may be associated with major depressive disorder.

Heat Shock Protein Family A Member 1B (Hspa1b) is an RNA binding protein that regulates transcriptional and post transcriptional processes. Previous studies have suggested its protective role in stress adaptation and post injury depression, as well as its potential therapeutic effects following antidepressant treatment in major depressive disorder (MDD). However, its direct involvement in MDD remains unclear. In this study, a mouse model with hippocampal Hspa1b overexpression was established. Integrated RNA immunoprecipitation sequencing (RIP seq) and RNA sequencing (RNA seq) were performed to investigate Hspa1b mediated transcriptional regulation and alternative splicing. Overexpression of Hspa1b resulted in 401 differentially expressed genes (DEGs), including downregulation of several neuroinflammatory genes such as Lcn2, Ccl5, and Cd52, upregulation of oxytocin/neurophysin I prepropeptide (Oxt), and downregulation of intercellular adhesion molecule 1 (Icam1), which are all associated with depression pathogenesis. In addition, 1,397 significantly altered Hspa1b regulated alternative splicing events were identified. RT qPCR confirmed splicing changes in six genes, including Spata13 and Ptpro, among others linked to depression and neuronal functions. These findings demonstrate that hippocampal Hspa1b overexpression is associated with transcriptional and splicing alterations in genes related to immune, neuronal, and HPA axis pathways, which are key mechanisms implicated in MDD. Based on these alterations, Hspa1b may act as a double-edged regulator in MDD, warranting further investigation of its causal role and therapeutic potential.