Dataset Information

Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder.

ABSTRACT: Major Depressive Disorder (MDD) is a common psychiatric disorder for which available medications are often not effective. The high prevalence of MDD and modest response to existing therapies compels efforts to better understand and treat the disorder. Decreased hippocampal volume with increasing duration of depression suggests altered gene expression or even a decrease in neurogenesis. Tissue punches from the dentate gyrus were collected postmortem from 23 subjects with MDD and 23 psychiatrically-normal control subjects. Total RNA was isolated and whole transcriptome paired-end RNA-sequencing was performed using an Illumina NextSeq 500. For each sample, raw RNA-seq reads were aligned to the Ensembl GRCh38 human reference genome. Analysis revealed 30 genes differentially expressed in MDD compared to controls (FDR<0.05). Down-regulated genes included several with inflammatory function (ISG15, IFI44L, IFI6, NR4A1/Nur-77) and GABBR1 while up-regulated genes included several with cytokine function (CCL2/MCP-1), inhibitors of angiogenesis (ADM, ADAMTS9), and the KANSL1 gene, a histone acetyltransferase. Similar analyses of specific subsets of MDD subjects (suicide vs. non-suicide, single vs. multiple episodes) yielded similar, though not identical, results. Enrichment analysis identified an over-representation of inflammatory and neurogenesis-related (ERK/MAPK) signaling pathways significantly altered in the hippocampal dentate gyrus in MDD. Together, these data implicate neuro-inflammation as playing a crucial role in MDD. These findings support continued efforts to identify adjunctive approaches towards the treatment of MDD with drugs including anti-inflammatory and neuroprotective properties.

SUBMITTER: Mahajan GJ

PROVIDER: S-EPMC5801125 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder.

Mahajan Gouri J GJ Vallender Eric J EJ Garrett Michael R MR Challagundla Lavanya L Overholser James C JC Jurjus George G Dieter Lesa L Syed Maryam M Romero Damian G DG Benghuzzi Hamed H Stockmeier Craig A CA

Progress in neuro-psychopharmacology & biological psychiatry 20171122

Major Depressive Disorder (MDD) is a common psychiatric disorder for which available medications are often not effective. The high prevalence of MDD and modest response to existing therapies compels efforts to better understand and treat the disorder. Decreased hippocampal volume with increasing duration of depression suggests altered gene expression or even a decrease in neurogenesis. Tissue punches from the dentate gyrus were collected postmortem from 23 subjects with MDD and 23 psychiatricall ...[more]

PMID: 29175309

Similar Datasets

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of anti-depressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated pro-inflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1?, TNF?, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients.

Dataset Information

Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder.

Publications

Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets