Altered Expression of Genes Involved in Inflammation and Apoptosis in Frontal Cortex in Major Depression

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Altered Expression of Genes Involved in Inflammation and Apoptosis in Frontal Cortex in Major Depression Molecular Psychiatry (2011) 16, 751–762 & 2011 Macmillan Publishers Limited All rights reserved 1359-4184/11 www.nature.com/mp ORIGINAL ARTICLE Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression RC Shelton1, J Claiborne1, M Sidoryk-Wegrzynowicz2, R Reddy1, M Aschner2, DA Lewis3 and K Mirnics4 1Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA; 2Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA; 3Departments of Psychiatry and Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA and 4Department of Psychiatry and the John F. Kennedy Center for Human Development, Vanderbilt University, Nashville, TN, USA 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 1a (IL-1a), IL-2, IL-3, IL-5, IL-8, IL-9, IL-10, IL-12A, IL-13, IL-15, IL-18, interferon gamma (IFNc), and lymphotoxin a (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. Molecular Psychiatry (2011) 16, 751–762; doi:10.1038/mp.2010.52; published online 18 May 2010 Keywords: major depression; microarray; inflammation; apoptosis; cytokines; oxidative stress Introduction agonal states, the presence of drugs or toxins;10,11 post-mortem factors such as the post-mortem interval A variety of brain imaging, post-mortem morpho- (PMI), pH, and RNA integrity; processing methods; metric, and other studies suggest that major depres- and other issues. Even when controlling for all of sion (MDD) involves abnormalities of cortico-limbic these variables, contemporary microarrays provide structures, including prefrontal cortex, anterior cingu- enormous amounts of data, creating challenges in 1 lated, amygdala, and hippocampus. In spite of the data handling. Further, MDD is not a unitary condi- fact that there is considerable evidence suggesting tion and is likely to comprise a range of clinical an underlying neurobiology for MDD, the molecular phenotypes and endophenotypes, which may affect basis has been elusive. A number of gene expression the results of microarray analysis. profiling studies in post-mortem brain tissue have This study was aimed at conducting gene expres- been conducted comparing depressed and control sion analysis of a brain area, Brodmann Area 10 2–9 samples, with variable results. Transcriptome pro- (BA10), which was chosen for several reasons. First, filing is a powerful, albeit complex, method, which is BA10 has been shown to be significantly involved in affected by a number of factors, including accuracy of the mediation of reward-related behavior, which is the pre-mortem diagnosis; peri-mortem characteris- central to the clinical phenomenology of depres- tics such as cause of death, the presence of prolonged sion.12 For example, Rogers et al.12 showed that a task, which involved choices between high probabil- Correspondence: Dr RC Shelton, Department of Psychiatry, ity and low reward versus low probability and high Vanderbilt University School of Medicine, 1500 21st Avenue, reward options resulted in the activation of three South, Suite 2200, Nashville, TN 37212, USA. adjacent regions in the orbito-frontal cortex, BA10, E-mail: [email protected] 15 Received 30 September 2009; revised 9 March 2010; accepted 12 BA11, and BA47 using [ O] positron emission April 2010; published online 18 May 2010 tomography. Cocaine13 and amphetamine,14 highly Transcriptome profiling in major depression RC Shelton et al 752 reinforcing substances, have also been shown to and as closely as possible for age (MDD = 47.2 produce activation of BA10. Kufahl et al.13 showed [s.d. = 14.0] and CTR = 48.9 [s.d. = 12.1], respectively), that cocaine administration resulted in decreased and PMI (17.8 [s.d. = 7.6] hours and 17.8 [s.d. = 6.5] fMRI brain oxygen-level-dependent signal in ventral hours, respectively) (all values mean±s.d.) (Table 1). tegmental area, nucleus accumbens, subcallosal cor- Depressed and control subject brain pH (6.59 tex, ventral pallidum, amygdala, parahippocampal [s.d. = 0.30] and 6.71 [s.d. = 0.26], respectively) and gyrus, posterior orbital gyrus, inferior and superior RNA integrity number ( > 7 for all subjects) were also temporal gyrus, but marked and sustained increases assessed (Table 1). There were no statistically sig- in brain oxygen-level-dependent signal in BA10 and nificant differences in age, PMI, pH, or RNA integrity 11. Similarly, amphetamine administration increased number between groups. All samples came from BA8 and 10 activities as measured by single photon persons free from all known psychotropic agents emission tomography.14 These data suggest that BA10 and recent substance abuse. Blood samples for is involved in reward and reinforcement processing, toxicology were obtained at the time of the brain a core dysfunction in depression.15,16 collection; all participants were confirmed to be free Only one earlier study has evaluated gene expres- of psychotropic medications except for one control sion in post-mortem tissue samples from BA10 in subject who tested positive for temazepam. Toxicol- MDD compared with controls.17 This study found 99 ogy results are listed in Table 1. The brain samples differentially expressed genes, which included sets of were collected through the local medical examiner’s transcripts of genes involved in cell proliferation. office and all patients died a non-hospitalized, acute Most of the altered genes are of unknown signifi- death, with virtually no agonal state that could bias cance with regard to MDD. However, one up-regulated the gene expression measurements. transcript, fibroblast growth factor receptor 1 (FGFR1), Field evaluations were conducted by trained and may be significant; the expression of both FGFR118 and experienced clinicians and consisted of structured its endogenous ligands FGF1 and FGF23 had earlier interviews with family members of the deceased. been shown to be altered in MDD samples. Written informed consent was obtained from all This study investigated post-mortem brain tissue participants. After field interviews were completed, samples from 14 depressed persons who were a committee of experienced research clinicians psychotropic drug free at the time of death and age- performed an independent diagnostic conference and sex-matched normal controls. Eleven of the 14 and assigned consensus DSM-IV diagnoses (including samples were from persons who met full DSM-IV depressive subtypes) for each subject on the basis of criteria for MDD, melancholic subtype antemortem. medical records and the results of structured inter- The melancholic subtype is a distinct clinical pheno- views conducted with family members of the de- type, characterized by symptoms of hyperarousal (for ceased. Eleven of the 14 depressed samples came example insomnia and anorexia) and hypothalamic– from persons with the melancholic subtype. pituitary–adrenal axis activation19 that may persist On receipt, the brains were dissected coronally, even after successful treatment.20 The Affymetrix flash frozen, and stored at À80 1C. An B5mm 5mm Exon 1.0 ST array was used for assessing expression gray matter cube from BA10 (spanning the cortical of gene transcripts using mRNA of high integrity. In gray matter) was carved out from the frozen block addition to the gene expression analysis, molecular using pre-chilled dental tools. This ensured a more pathways of interest were evaluated using Gene homogenous sample, greatly diminishing harvesting Set Enrichment Analysis (GSEA) to determine altered bias (variable white matter/gray matter ratio) and expression of sets of genes implicated in depression. reducing experimental noise in our dataset. Further- The results showed altered expression of a large num- more, this approach allowed us to preferentially ber of genes, but specifically showed up-regulation detect expression changes in neuron- and glia- of the expression of pro- and anti-inflammatory enriched tissue. The tissue piece was immediately cytokines and specific anti-apoptotic factors. placed in cold Trizol reagent, homogenized and used for RNA extraction.21 Materials and methods Design and processing of
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