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

Abstract

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), 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.

Comparison of plasma MicroRNA levels in drug naive, first episode depressed patients and healthy controls

“…Additionally, another postmortem study demonstrated the down-regulation of SLC17A7 mRNA expression in the entorhinal cortex of depressed patients (Uezato et al, 2009). Several studies have also demonstrated the importance of SLC17A7 downregulation in depression (Tordera et al, 2007(Tordera et al, , 2011GarciaeGarcia et al, 2009;Balschun et al, 2010). miR-451a upregulation has been predicted to be related to the downregulation of SLC17A7, which suggests a potential interaction with glutamatergic pathways.…”

Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity

“…As previously described by Tordera et al, 2011), for each tissue sample, 500 ng of reverse-transcribed RNA were diluted to 50 μL with sterile water, combined with an equal volume of TaqMan Universal PCR Master Mix (2 Â ; Applied Biosystems, Foster City, CA, USA), mixed by inversion, and spun briefly in an Eppendorfs 5415 C microcentrifuge (Brinkmann Instruments, Westbury, NY, USA). After TLDAs were brought to room temperature, 100 μL master mix were loaded into each port connected to reaction wells.…”

Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive–compulsive disorder as an example of overlapping clinical and genetic heterogeneity

“…In addition, G Â E approaches have used non-human primate polymorphisms and gene-targeted rodents to evaluate, for example, serotonin-related genes such as Slc6a4 and the effects of SRI treatment on anxiety-and depressive-like behaviours [77,154,158,159]. Gene-targeted and other mouse models have also been used to dissect specific brain regions and neurocircuitry patterns involved in anxiety-like, depression-like and OCD-related behaviours [160][161][162].…”