Chronic stress and impaired glutamate function elicit a depressive-like phenotype and common changes in gene expression in the mouse frontal cortex

Department of Pharmacology, University of Navarra, 31080 Pamplona, Spain.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology (Impact Factor: 4.37). 10/2010; 21(1):23-32. DOI: 10.1016/j.euroneuro.2010.06.016
Source: PubMed


Major depression might originate from both environmental and genetic risk factors. The environmental chronic mild stress (CMS) model mimics some environmental factors contributing to human depression and induces anhedonia and helplessness. Mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1) have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, gene expression changes in the frontal cortex, common to stress and impaired glutamate function. Both VGLUT1(+/-) and CMS mice showed helpless and anhedonic-like behavior. Microarray studies in VGLUT1(+/-) mice revealed regulation of genes involved in apoptosis, neurogenesis, synaptic transmission, protein metabolic process or learning and memory. In addition, RT-PCR studies confirmed gene expression changes in several glutamate, GABA, dopamine and serotonin neurotransmitter receptors. On the other hand, CMS affected the regulation of 147 transcripts, some of them involved in response to stress and oxidoreductase activity. Interestingly, 52 genes were similarly regulated in both models. Specifically, a dowregulation in genes that promote cell proliferation (Anapc7), cell growth (CsnK1g1), cell survival (Hdac3), and inhibition of apoptosis (Dido1) was observed. Genes linked to cytoskeleton (Hspg2, Invs), psychiatric disorders (Grin1, MapK12) or an antioxidant enzyme (Gpx2) were also downregulated. Moreover, genes that inhibit the MAPK pathways (Dusp14), stimulate oxidative metabolism (Eif4a2) and enhance glutamate transmission (Rab8b) were upregulated. We suggest that these genes could form part of the altered "molecular context" underlying depressive-like behaviour in animal models. The clinical relevance of these findings is discussed.

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Available from: María Javier Ramírez, Sep 30, 2015
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    • "decline observed in adulthood . Our results are in agreement with specific aspects of this previous study and also show a transient induction in mPFC of Hdac3 expression restricted to postnatal life . Interestingly , in contrast to the upregulation we observed with Hdac3 levels , adult - onset stress evoked a decline in cortical Hdac3 expression ( Tordera et al . , 2011 ) , suggesting that the nature of regulation of Hdac3 by stress is dependent on the temporal window of stress experi - ence . The differences noted in the pattern of gene regulation across these studies could also arise due to differences in brain regions studied and species - specific effects . It will be important to uncover whether t"
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    ABSTRACT: Early stress has been hypothesized to recruit epigenetic mechanisms to mediate persistent molecular, cellular, and behavioral changes. Here, we have examined the consequence of the early life stress of maternal separation (ES) on the gene expression of several histone modifiers that regulate histone acetylation and methylation within the medial prefrontal cortex (mPFC), a key limbic brain region that regulates stress responses and mood-related behavior. ES animals exhibit gene regulation of both writer (histone acetyltransferases and histone methyltransferases) and eraser (histone deacetylases and histone lysine demethylases) classes of histone modifiers. While specific histone modifiers (Kat2a, Smyd3, and Suv420h1) and the sirtuin, Sirt4 were downregulated across life within the mPFC of ES animals, namely at postnatal Day 21, 2 months, and 15 months of age, we also observed gene regulation restricted to these specific time points. Despite the decline noted in expression of several histone modifiers within the mPFC following ES, this was not accompanied by any change in global or residue-specific H3 acetylation and methylation. Our findings indicate that ES results in the regulation of several histone modifiers within the mPFC across life, and suggest that such perturbations may contribute to the altered prefrontal structural and functional plasticity observed following early adversity. © 2015 Wiley Periodicals, Inc. Dev Psychobiol.
    Developmental Psychobiology 09/2015; DOI:10.1002/dev.21365 · 3.31 Impact Factor
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    • "Another recent study using Western blot analysis on postmortem frontal cortex samples (BA 8 and 9) from the SNC collection has also shown that levels of MEK1, MEK2, CREB, and Rap1 are significantly reduced in individuals with MDD (Yuan et al. 2010). A microarray study using environmental (chronic mild stress) and genetic (VGLUT ?/-heterozygous mice) animal models of depression revealed that MAPK12 was down-regulated, whereas the genes responsible for inhibiting the MAPK pathways [dual specificity phosphatase 14 (DUSP14)], stimulating oxidative metabolism [eukaryotic translation initiation factor 4A2 (EIF4A2)], and enhancing glutamate transmission (RAB8B, member RAS oncogene family) were up-regulated in the frontal cortex in both experimental models (Tordera et al. 2011). In addition, antidepressants alleviated depressive-like behaviors and reversed the attenuation of the MEK/ERK pathway in the frontal cortex of stressed rats (Qi et al. 2008, 2009). "
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    ABSTRACT: Previous human postmortem studies have shown that expression of glutamate transporters (SLC1A2 and SLC1A3) and gamma-aminobutyric acid-synthesizing enzyme [glutamic acid decarboxylase 1 (GAD1)] are reduced in the dorsolateral prefrontal cortex (dlPFC) in subjects with major depressive disorder (MDD). However, no studies have explored the association between these two molecules and its related biological processes in MDD because of limited postmortem sample availability. Data sharing using the Stanley neuropathology consortium integrative database (SNCID), a web-based tool that integrates datasets from the same postmortem brain samples, allowed us to reanalyze existing postmortem data efficiently. We found two datasets where the mRNA levels of GAD1 and SLC1A2 in subregions of the dlPFC were significantly and marginally lower in subjects with MDD (n = 15) than in controls (n = 15) (p = 0.045 and 0.057, respectively). In addition, there was a positive correlation between these two molecules (n = 30, p < 0.05). Spearman's rank correlation analysis using all available datasets revealed that the expression levels of both GAD1 and SLC1A2 mRNAs were commonly correlated with the expression levels of several neuropathological markers in the dlPFC in all of the SNCID subjects (n = 60, p < 0.001). Most of these markers are known to be involved in the RAF/MEK/ERK signal transduction pathway. This exploratory study provides an initial step for future studies to investigate an association between the reductions in SLC1A2 and GAD1 mRNA expression and their relation to the attenuation of the RAF/MEK/ERK signaling pathway in the dlPFC in MDD. The integration of the existing archival data may shed light on one important aspect of the pathophysiology of MDD.
    Journal of Neural Transmission 03/2014; 121(7). DOI:10.1007/s00702-014-1189-z · 2.40 Impact Factor
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    • "The differences in these studies may reflect structural and temporal specificity of the serotoninergic response to stress over time. However, overall a change in SERT expression within the CNS in both chronic stress and depression is supported elsewhere (Murrough et al., 2011; Tordera et al., 2011; Kohut et al., 2012; Nikolaus et al., 2012). It is possible that during the first stages of depression, or experimental induction of a depressive-like state in animal models, SERT function is increased because of enhanced serotonin release, but longer-lasting over-expression of SERT in susceptible individuals' results in lower serotonin activity at later time points. "
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    ABSTRACT: A chronic stress paradigm comprising exposure to predation, tail suspension and restraint induces a depressive syndrome in C57BL/6J mice that occurs in some, but not all, animals. Here, we sought to extend our behavioural studies to investigate how susceptibility (sucrose preference < 65%) or resilience (sucrose preference > 65%) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes. All chronically stressed animals, displayed increased level of anxiety, but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrated hyperactivity under stressful lighting conditions. These changes were not present in resilient or acutely stressed animals. Compared to resilient animals, susceptible mice showed elevated expression of tumour necrosis factor alpha (TNF) and the 5-HT transporter (SERT) in the pre-frontal area. Enhanced expression of 5HT(2A) and COX-1 in the pre-frontal area was observed in all stressed animals. In turn, indoleamine-2,3-dioxygenase (IDO) was significantly unregulated in the raphe of susceptible animals. At the cellular level, increased numbers of Iba-1-positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals. Consequently, the susceptible animals display a unique molecular profile when compared to resilient, but anxious, animals, unexpectedly, this altered profile provides a rationale for exploring anti-inflammatory, and possibly, TNF-targeted therapy for major depression.
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