TY - JOUR
T1 - Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia
AU - Scheepstra, Karel W. F.
AU - Mizee, Mark R.
AU - van Scheppingen, Jackelien
AU - Adelia, Adelia
AU - Wever, Dennis D.
AU - Mason, Matthew R. J.
AU - Dubbelaar, Marissa L.
AU - Hsiao, Cheng-Chih
AU - Eggen, Bart J. L.
AU - Hamann, J. rg
AU - Huitinga, Inge
N1 - Funding Information: The Netherlands Brain Bank for Psychiatry ( https://www.brainbank.nl/nbb-psy/ ) is funded by Grant No. 240–921200 from the Netherlands Organization for Scientific Research. Funding Information: The Netherlands Brain Bank for Psychiatry ( https://www.brainbank.nl/nbb-psy/) is funded by Grant No. 240–921200 from the Netherlands Organization for Scientific Research. We thank the Psychiatric Donor Program of the Netherlands Brain Bank team for their excellent support and the donors for their valuable donation. A previous version of this article was published as a preprint on medRxiv: https://doi.org/10.1101/2023.01.11.23284393. After acceptance, the RNA sequencing dataset will be available online in the Gene Expression Omnibus database. The authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2023 Society of Biological Psychiatry
PY - 2023/10/15
Y1 - 2023/10/15
N2 - 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.
AB - 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.
KW - Depression
KW - Microglia
KW - Psychiatry
KW - RNA sequencing
KW - Synaptosomes
UR - http://www.scopus.com/inward/record.url?scp=85165314309&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.biopsych.2023.04.020
DO - https://doi.org/10.1016/j.biopsych.2023.04.020
M3 - Article
C2 - 37121366
SN - 0006-3223
VL - 94
SP - 619
EP - 629
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 8
ER -