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: 14.5). 08/2007; 12(7):640-55. DOI: 10.1038/
Source: PubMed


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.

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Available from: Adolfo Sequeira
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    • "In this study, an exploratory whole-genome approach (Affymetrix HG-U133A cDNA microarray) identified low SAT1 mRNA levels in suicides, and low mRNA and protein levels were confirmed by semiquantitative reverse transcription–polymerase chain reaction (RT–PCR), immunohistochemistry and Western blot analyses (Sequeira et al., 2006). Low SAT1 expression in the brain has been confirmed by other groups in both depressed and non-depressed suicides (Sequeira et al., 2007; Guipponi et al., 2009; Klempan et al., 2009a,b). Conversely, higher SAT1 has been found in the blood of suicidal attempters, non-attempters who are suicide ideators and suicides with bipolar disorder or psychosis (Le-Niculescu et al., 2013), providing further evidence for a role of SAT1 dysregulation in suicidal behavior. "
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    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.
    Full-text · Article · May 2015 · Neurobiology of Disease
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    • "However, significant evidence suggests that deficits in GABAergic transmission may play a key role in MDD. The evidence from patients pointing to compromised GABAergic transmission in MDD includes reduced brain concentrations of GABA (Sanacora et al., 1999; Hasler et al., 2007; Gabbay et al., 2012), reduced expression of the GABAsynthesizing enzyme glutamic acid decarboxylase (GAD67) (Karolewicz et al., 2010; Guilloux et al., 2012), altered expression of GABA A receptors (GABA A Rs) (Merali et al., 2004; Choudary et al., 2005; Sequeira et al., 2007; Klempan et al., 2009; Klumpers et al., 2010), compromised function or loss of GABAergic interneurons (Rajkowska et al., 2007; Maciag et al., 2010; Sibille et al., 2011) and marked functional deficits in cortical inhibition (Levinson et al., 2010). Conversely, antidepressant drugs (Sanacora et al., 2002; Kucukibrahimoglu et al., 2009) and electroconvulsive therapy (Sanacora et al., 2003) can normalize the reduced GABA concentrations in brain and plasma of MDD patients [for review see (Croarkin et al., 2011; Luscher et al., 2011)]. "
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    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.
    Full-text · Article · Aug 2014 · Neuropharmacology
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    • "Although nothing is known about gene expression in the CP in MDD subjects, a significant amount of literature has previously focused on the role of the hippocampus. For example, there is evidence for altered gene expression in the human post-mortem hippocampus in individuals with MDD (Sequeira et al., 2007, 2009). However, gene expression studies should be interpreted with caution, as hippocampal dissections also likely contain CP. "
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    ABSTRACT: Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus (CP), the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the CP at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled, and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p < 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFβ) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the CP in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.
    Full-text · Article · Apr 2014 · Frontiers in Human Neuroscience
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