Alterations in gene expression and protein levels of extracellular matrix-related molecules in major depressive disorder: Insights from analyses in the hippocampus and prefrontal cortex

Major depressive disorder (MDD) is the leading cause of disability worldwide and shows marked sex differences in prevalence and symptomatology. The dorsolateral prefrontal cortex (DLPFC) and hippocampus are key regions implicated in MDD, yet the role of extracellular matrix (ECM) dysregulation in these areas remains unclear. The ECM supports neural plasticity and synaptic stability through chondroitin sulfate proteoglycans (CSPGs), remodeling enzymes, and adhesion molecules, and its disruption has been linked to psychiatric disorders. In this study, we examined postmortem DLPFC and hippocampal tissue from 20 individuals with MDD and 20 controls to assess expression of ECM-related genes (BCAN, NCAN, VCAN, ADAMTS1, ADAMTS8, CSGALNACT1, SEMA3A, TNR, ST8SIA4). Protein levels of ADAMTS8, SEMA3A, and ST8SIA4 were further examined by Western blotting. We observed that ADAMTS8 expression was significantly reduced in the DLPFC of individuals with MDD, indicating potential impairments in ECM remodeling. Sex-stratified analyses revealed decreased SEMA3A expression in males with MDD and a trend toward reduced ST8SIA4 expression in females. At the protein level, SEMA3A was increased in the DLPFC but decreased in the hippocampus when both sexes were analyzed together, suggesting region-specific or post-transcriptional regulation. Notably, SEMA3A protein levels were significantly increased in males within the DLPFC, with a trend toward decrease in males in the hippocampus. ST8SIA4 protein expression was also reduced in the DLPFC in MDD. These findings identify alterations in ECM-related gene and protein expression in MDD, supporting a role for impaired ECM remodeling and synaptic plasticity in the disorder and highlighting the ECM as a promising therapeutic target.