Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray 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 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.

Prenatal NeuN+ neurons of Down syndrome display aberrant integrative DNA methylation and gene expression profiles.

Aim: To detect expression quantitative trait methylation (eQTM) loci within the cerebrum of prenatal Down syndrome (DS) and controls. Material & methods: DNA methylation gene expression profiles were acquired from NeuN+ nuclei, obtained from cerebrum sections of DS and controls. Linear regression models were applied to both datasets and were subsequently applied in an integrative analysis model to detect DS-associated eQTM loci. Results & conclusion: Widespread aberrant DNA methylation and gene expression were observed in DS. A substantial number of differentially methylated loci were replicated according to a previously reported study. Subsequent integrative analyses (eQTM) yielded numerous associated DS loci. the authors associated DNA methylation, gene expression and eQTM loci with DS that may underlie particular DS phenotypical characteristics.

Down syndrome (DS) is a common (1 of 1000 live births) autosomal aneuploidy in humans. Epigenetic programming regulates gene expression, defines cell fate and differentiation and drives early development. The authors aimed to detect DNA loci that are linked with the early developing brain of DS by analyzing DNA methylation and gene expression in prenatal DS neuronal samples. Numerous differential DNA methylated and expressed loci were found to be linked with DS. These findings may underlie particular DS characteristics, yet follow-up confirmation is required.