Single-nucleus RNA sequencing uncovers metabolic dysregulation in the prefrontal cortex of major depressive disorder patients

Major depressive disorder (MDD) is a widespread psychiatric condition, recognized as the third leading cause of global disease burden in 2008. In the context of MDD, alterations in synaptic transmission within the prefrontal cortex (PFC) are associated with PFC hypoactivation, a key factor in cognitive function and mood regulation. Given the high energy demands of the central nervous system, these synaptic changes suggest a metabolic imbalance within the PFC of MDD patients. However, the cellular mechanisms underlying this metabolic dysregulation remain not fully elucidated. This study employs single-nucleus RNA sequencing (snRNA-seq) data to predict metabolic alterations in the dorsolateral PFC (DLPFC) of MDD patients. Our analysis revealed cell type-specific metabolic patterns, notably the disruption of oxidative phosphorylation and carbohydrate metabolism in the DLPFC of MDD patients. Gene set enrichment analysis based on human phenotype ontology predicted alterations in serum lactate levels in MDD patients, corroborated by the observed decrease in lactate levels in MDD patients compared to 47 age-matched healthy controls (HCs). This transcriptional analysis offers novel insights into the metabolic disturbances associated with MDD and the energy dynamics underlying DLPFC hypoactivation. These findings are instrumental for comprehending the pathophysiology of MDD and may guide the development of innovative therapeutic strategies.