Overexpression of Hspa1b in the Mouse Hippocampus Is Associated with Major Depressive Disorder

Heat Shock Protein Family A Member 1B ( Hspa1b ) is an RNA-binding protein (RBP), which is essential for transcriptional regulation and post-transcriptional control of RNAs. While previous studies have demonstrated its protective role in stress adaptation and post-injury depression, its function in major depressive disorder (MDD) remains unclear. To investigate the role of Hspa1b in MDD, we established a mouse model with hippocampal Hspa1b overexpression. Integrated RNA immunoprecipitation sequencing (iRIP-seq) and RNA-seq were employed to analyze Hspa1b -mediated transcriptional regulation and alternative splicing. The overexpression of Hspa1b in mouse hippocampal tissue resulted in significant differential expression of 401 genes (fold-change > 2 or < 0.5, FDR P-value < 0.05). Among these genes, 69 genes were upregulated, including oxytocin/neurophysin I prepropeptide (Oxt) , which has demonstrated strong antidepressant effects. Conversely, 332 genes were downregulated, particularly intercellular adhesion molecule-1 ( Icam-1 ), which is associated with depression. Gene Ontology analysis revealed that differentially expressed genes were enriched in immune and inflammation-related biological processes. Additionally, 1,397 Hspa1b -regulated alternative splicing events (RASEs) were identified (P < 0.05), with significant enrichment in SPATA13 , a gene linked to MDD. This study is the first to demonstrate an association between Hspa1b overexpression in the mouse hippocampus and MDD, potentially through its RNA-binding capacity. Further research is needed to explore the causal relationship and evaluate its therapeutic potential in MDD.