A Molecular Signature of Depression in the Amygdala

University of Tours, Tours, Centre, France
American Journal of Psychiatry (Impact Factor: 12.3). 08/2009; 166(9):1011-24. DOI: 10.1176/appi.ajp.2009.08121760
Source: PubMed


Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Recent gene array attempts to identify the molecular underpinnings of the illness in human postmortem subjects have not yielded a consensus. The authors hypothesized that controlling several sources of clinical and technical variability and supporting their analysis with array results from a parallel study in the unpredictable chronic mild stress (UCMS) rodent model of depression would facilitate identification of the molecular pathology of major depression.
Large-scale gene expression was monitored in postmortem tissue from the anterior cingulate cortex and amygdala in paired male subjects with familial major depression and matched control subjects without major depression (N=14-16 pairs). Area dissections and analytical approaches were optimized. Results from the major depression group were compared with those from the UCMS study and confirmed by quantitative polymerase chain reaction and Western blot. Gene coexpression network analysis was performed on transcripts with conserved major depression-UCMS effects.
Significant and bidirectional predictions of altered gene expression were identified in amygdala between major depression and the UCMS model of depression. These effects were detected at the group level and also identified a subgroup of depressed subjects with a more homogeneous molecular pathology. This phylogenetically conserved "molecular signature" of major depression was reversed by antidepressants in mice, identified two distinct oligodendrocyte and neuronal phenotypes, and participated in highly cohesive and interactive gene coexpression networks.
These studies demonstrate that the biological liability to major depression is reflected in a persistent molecular pathology that affects the amygdala, and support the hypothesis of maladaptive changes in this brain region as a putative primary pathology in major depression.

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Available from: Alexandre Surget, Feb 17, 2014
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    • "The absence of any more striking or widespread volume difference is perhaps not surprising in light of the mixed imaging literature on whole amygdala volume in depression (e.g., Lange and Irle 2004; Malykhin et al. 2012; Hastings et al. 2004; Sheline et al. 1998). Variables not examined in the current study that may also contribute to a larger lateral nucleus in MDD include an increase in dendritic material and spines (Vyas et al. 2002; Sibille et al. 2009), as seen in the BLA of rats under prolonged stress (Vyas et al. 2002, 2006). Theoretically, increased amygdala activity in MDD (Carlson et al. 2006; Drevets et al. 2008) may result in an increase in BLA synapses and potentially a concomitant increase in perisynaptic glia (He Fig. 3 Greater number of basolateral amygdala neurovascular cells in major depressive disorder. "
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    • "Analysis of promoter transcription factor enrichment was performed with Enrichr (Chen et al, 2013). Real-time quantitative polymerase chain reaction (qPCR) was performed on a Mastercycler real-time PCR machine (Eppendorf, Hamburg, Germany) using universal PCR conditions (Sibille et al, 2009). Differential expression was analyzed by random intercept model with variable selection using Bayesian information criteria and class label permutation (Wang et al, 2012). "
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    • "Importantly, these same regions exhibit altered structurefunction-molecular genetic changes in depression e.g. (Disner et al., 2011; Mayberg, 2003; Price and Drevets, 2010; Savitz et al., 2013; Sibille et al., 2009). The experiment was conducted using next generation sequencing, and genes that were expressed above a threshold level and were significantly altered in their expression in CSD versus CON mice were subjected to pathway analysis to identify the processes and pathways with which they are most commonly associated and their upstream regulators. "
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