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Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder
Gouri J Mahajan1, Eric J Vallender1, Michael R Garrett2
1Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
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.
Insights
Major Depressive Disorder (MDD) involves altered gene expression in the hippocampus, implicating neuroinflammation. This suggests new treatments targeting inflammation and neuroprotection may be beneficial for MDD patients.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- Major Depressive Disorder (MDD) affects many individuals, with limited treatment efficacy.
- Reduced hippocampal volume in depression suggests changes in gene expression and neurogenesis.
Purpose of the Study:
- To investigate gene expression differences in the hippocampal dentate gyrus of MDD subjects.
- To identify molecular pathways altered in the brain during Major Depressive Disorder.
Main Methods:
- Postmortem tissue from 23 MDD subjects and 23 controls was analyzed using whole transcriptome RNA sequencing.
- Differential gene expression and pathway enrichment analyses were performed on RNA-seq data.
Main Results:
- 30 genes were found to be differentially expressed in MDD subjects compared to controls (FDR<0.05).
- Key altered genes included those involved in inflammation, cytokine function, and angiogenesis.
- Enrichment analysis revealed significant alterations in inflammatory and neurogenesis-related (ERK/MAPK) signaling pathways.
Conclusions:
- Neuroinflammation plays a significant role in the pathophysiology of Major Depressive Disorder.
- Findings support the development of adjunctive MDD therapies with anti-inflammatory and neuroprotective properties.
