Prefrontal cortex astrocytes in major depressive disorder: exploring pathogenic mechanisms and potential therapeutic targets

Abstract

Major depressive disorder (MDD) is a prevalent mental health condition characterized by persistent feelings of sadness and hopelessness, affecting millions globally. The precise molecular mechanisms underlying MDD remain elusive, necessitating comprehensive investigations. Our study integrates transcriptomic analysis, functional assays, and computational modeling to explore the molecular landscape of MDD, focusing on the DLPFC. We identify key genomic alterations and co-expression modules associated with MDD, highlighting potential therapeutic targets. Functional enrichment and protein–protein interaction analyses emphasize the role of astrocytes in MDD progression. Machine learning is employed to develop a predictive model for MDD risk assessment. Single-cell and spatial transcriptomic analyses provide insights into cell type–specific expression patterns, particularly regarding astrocytes. We have identified significant genomic alterations and co-expression modules associated with MDD in the DLPFC. Key genes involved in neuroactive ligand-receptor interaction pathways, notably in astrocytes, have been highlighted. Additionally, we developed a predictive model for MDD risk assessment based on selected key genes. Single-cell and spatial transcriptomic analyses underscored the role of astrocytes in MDD. Virtual screening of compounds targeting GPR37L1, KCNJ10, and PPP1R3C proteins has identified potential therapeutic candidates. In summary, our comprehensive approach enhances the understanding of MDD’s molecular underpinnings and offers promising opportunities for advancing therapeutic interventions, ultimately aiming to alleviate the burden of this debilitating mental health condition.

Key messages

• Our investigation furnishes insightful revelations concerning the dysregulation of astrocyte-associated processes in MDD.

• We have pinpointed specific genes, namely KCNJ10, PPP1R3C, and GPR37L1, as potential candidates warranting further exploration and therapeutic intervention.

• We incorporate a virtual screening of small molecule compounds targeting KCNJ10, PPP1R3C, and GPR37L1, presenting a promising trajectory for drug discovery in MDD.