Article

Patterns of gene expression in the limbic system of suicides with and without major depression

McGill Group for Suicide Studies, Douglas Hospital, McGill University, Montreal, QC, Canada.
Molecular Psychiatry (Impact Factor: 15.15). 08/2007; 12(7):640-55. DOI: 10.1038/sj.mp.4001969
Source: PubMed

ABSTRACT The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides=18, non depressed suicides=8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.

Download full-text

Full-text

Available from: Adolfo Sequeira, Jun 19, 2015
0 Followers
 · 
225 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Low brain expression of the spermidine/spermine N-1 acetyltransferase (SAT1) gene, the rate-limiting enzyme involved in catabolism of polyamines that mediate the polyamine stress response (PSR), has been reported in depressed suicides. However, it is unknown whether this effect is associated with depression or with suicide and whether all or only specific isoforms expressed by SAT1, such as the primary 171 amino acid protein-encoding transcript (SSAT), or an alternative splice variant (SSATX) that is involved in SAT1 regulated unproductive splicing and transcription (RUST), are involved. We applied next generation sequencing (RNA-seq) to assess gene-level, isoform-level, and exon-level SAT1 expression differences between healthy controls (HC, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9, BA9) of medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA species putatively involved in SAT1 post-transcriptional regulation. A DSM-IV diagnosis was made by structured interview. Toxicology and history ruled out recent psychotropic medication. At the gene-level, we found low SAT1 expression in both MDD-S (vs. HC, p=0.002) and MDD (vs. HC, p=0.002). At the isoform-level, reductions in MDD-S (vs. HC) were most pronounced in four transcripts including SSAT and SSATX, while reductions in MDD (vs. HC) was pronounced in three transcripts, one of which was reduced in MDD relative to MDD-S (all p<0.1 FDR corrected). We did not observe evidence for differential exon-usage (i.e. splicing) nor differences in miRNA expression. Results replicate the finding of low SAT1 brain expression in depressed suicides in an independent sample and implicate low SAT1 brain expression in MDD independent of suicide. Low expression of both SSAT and SATX isoforms suggest shared transcriptional mechanisms involved in RUST may account for low SAT1 brain expression in depressed suicides. Future studies are required to understand the functions and regulation of SAT1 isoforms, and how they relate to the pathogenesis of MDD and suicide. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 05/2015; 79. DOI:10.1016/j.nbd.2015.04.014 · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mice that were rendered heterozygous for the γ2 subunit of GABAA receptors (γ2(+/-) mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The γ2(+/-) model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that γ2(+/-) mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical γ2(+/-) neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of γ2(+/-) mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of γ2(+/-) mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder.
    Neuropharmacology 08/2014; 88. DOI:10.1016/j.neuropharm.2014.07.019 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in the post-transcriptional regulation of mRNA. These molecules have been the subject of growing interest as they are believed to control the regulation of a large number of genes, including those expressed in the brain. Evidence suggests that miRNAs could be involved in the pathogenesis of neuropsychiatric disorders. Alterations in metabolic enzymes of the polyamine system have been reported to play a role in predisposition to suicidal behaviour. We have previously shown the expression of the polyamine genes SAT1 and SMOX to be down-regulated in the brains of suicide completers. In this study, we hypothesized that the dysregulation of these genes in depressed suicide completers could be influenced by miRNA post-transcriptional regulation. Using a stringent target prediction analysis, we identified several miRNAs that target the 3'UTR of SAT1 and SMOX. We profiled the expression of 10 miRNAs in the prefrontal cortex (BA44) of suicide completers (N = 15) and controls (N = 16) using qRT-PCR. We found that several miRNAs showed significant up-regulation in the prefrontal cortex of suicide completers compared to psychiatric healthy controls. Furthermore, we demonstrated a significant correlation between these miRNAs and the expression levels of both SAT1 and SMOX. Our results suggest a relationship between miRNAs and polyamine gene expression in the suicide brain, and postulate a mechanism for SAT1 and SMOX down-regulation by post-transcriptional activity of miRNAs.
    The International Journal of Neuropsychopharmacology 09/2013; 17(01):1-10. DOI:10.1017/S1461145713000941 · 5.26 Impact Factor