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
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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.

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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.
    Neurobiology of Disease 05/2015; 79. DOI:10.1016/j.nbd.2015.04.014 · 5.20 Impact Factor
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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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    Neuropharmacology 08/2014; 88. DOI:10.1016/j.neuropharm.2014.07.019 · 4.82 Impact Factor
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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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