Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression

Abstract

The etiology of major depression (MDD), a common and complex disorder, remains obscure. Gene expression profiling was conducted on post-mortem brain tissue samples from Brodmann Area 10 (BA10) in the prefrontal cortex from psychotropic drug-free persons with a history of MDD and age, gender, and post-mortem interval-matched normal controls (n=14 pairs of subjects). Microarray analysis was conducted using the Affymetrix Exon 1.0 ST arrays. A set of differential expression changes was determined by dual-fold change-probability criteria (∣average log ratios∣>0.585 [equivalent to a 1.5-fold difference in either direction], P<0.01), whereas molecular pathways of interest were evaluated using Gene Set Enrichment Analysis software. The results strongly implicate increased apoptotic stress in the samples from the MDD group. Three anti-apoptotic factors, Y-box-binding protein 1, caspase-1 dominant-negative inhibitor pseudo-ICE, and the putative apoptosis inhibitor FKGS2, were over-expressed. Gene set analysis suggested up-regulation of a variety of pro- and anti-inflammatory cytokines, including interleukin 1α (IL-1α), IL-2, IL-3, IL-5, IL-8, IL-9, IL-10, IL-12A, IL-13, IL-15, IL-18, interferon gamma (IFNγ), and lymphotoxin α (TNF superfamily member 1). The genes showing reduced expression included metallothionein 1M (MT1M), a zinc-binding protein with a significant function in the modulation of oxidative stress. The results of this study indicate that post-mortem brain tissue samples from BA10, a region that is involved in reward-related behavior, show evidence of local inflammatory, apoptotic, and oxidative stress in MDD.

Figure 1. Hierarchical clustering of differentially expressed genes

Normalized log2 intensities were clustered by GenePattern in two dimensions (horizontal: genes; vertical: samples [purple=MDD, green=controls]) on the basis of Euclidian distance. Each colored pixel represents a single gene expression value in one subject. The color intensity is proportional to its relative expression level (blue: under expressed; red: over expressed). Note that the statistical segregation of depressed and control subjects are almost complete, with an overlap of only two controls. Labels on the right denote gene symbols and probe identifiers. For more data, see Table 2.

Figure 2. qPCR Analysis of selected cytokine-related mRNAs in MDD subjects and matched controls

X axis denotes microarray-reported expression differences (ALR), while Y axis shows qPCR-obtained differential expression values (ΔΔCt) for 10 selected transcripts. Each symbol represents a different gene, denoted in the figure legend. Note that all the observations occupy quadrants 2–3 (and no observations are located in quadrants 1 and 4), showing that all microarray-qPCR results were concordant in directionality of change. The ALR-ΔΔCt results were highly correlated (r=0.92; p < 0.001).