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Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia
Karel W F Scheepstra1, Mark R Mizee2, Jackelien van Scheppingen2
1Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands; Psychiatric Program of the Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands; Department of Psychiatry, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, the Netherlands.
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 gray matter (GM) and corpus callosum white matter of 13 donors with MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry staining. Because gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by reverse transcriptase-quantitative polymerase chain reaction and Western blot.
Results:
Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from white matter in donors with MDD, compared with control donors. Of these, 81 genes were less abundantly expressed in GM in 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. Immunohistochemistry staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p = .0009) and CD47 (p = .068) messenger RNA, and CD47 protein was significantly elevated (p = .0396) in synaptic fractions of MDD cases.
Conclusions:
Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD that is possibly caused by neuronal regulation.
Insights
Microglia in major depressive disorder (MDD) show an immune-suppressed gene expression profile in gray matter. This suggests neuronal regulation may contribute to MDD pathophysiology.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are implicated in major depressive disorder (MDD) pathophysiology.
- Biological mechanisms linking microglia and MDD remain largely unknown.
- This study investigates microglial gene expression in MDD.
Purpose of the Study:
- To investigate the gene expression profile of microglial cells in major depressive disorder (MDD).
- To explore the relationship between microglial gene expression and neuronal regulators of microglia activity in MDD.
- To identify potential biological mechanisms underlying MDD pathophysiology.
Main Methods:
- Isolated pure microglia from autopsy brain samples (gray matter and white matter) of MDD and control donors.
- Performed RNA sequencing to analyze gene expression profiles.
- Validated top differentially expressed genes using immunohistochemistry and Western blot.
Main Results:
- Identified 92 differentially expressed genes in gray matter microglia from MDD donors, with 81 genes showing decreased expression.
- Observed downregulation of pathways related to complement system and phagocytosis in MDD microglia.
- Found increased expression of CD200 mRNA and CD47 mRNA and protein in MDD cases.
Conclusions:
- MDD is associated with an immune-suppressed microglial phenotype in gray matter.
- Neuronal regulation may contribute to the observed immune-suppressed microglial phenotype in MDD.
- These findings provide insights into the role of microglia in MDD pathogenesis.
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