Microglia transcriptional profiling in major depressive disorder shows inhibition of cortical grey matter microglia

BACKGROUND: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains.

METHODS: Pure, intact microglia were isolated at brain autopsy from occipital cortex grey matter (GM) and corpus callosum white matter (WM) of 13 MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry (IHC) staining. Since gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by RT-qPCR and Western blot.

RESULTS: Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from WM in MDD, compared to controls. Of these, 81 genes were less abundantly expressed in GM MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis were differentially regulated in GM microglia in MDD. IHC staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p+0.0009) and CD47 (p=0.068) mRNA, and CD47 protein was significantly elevated (p=0.0396) in synaptic fractions of MDD cases.

CONCLUSIONS: Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD, possibly caused by neuronal regulation.