Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1

Abstract

1These authors contributed equally to this study.Abbreviations used: Arc, activity regulated cytoskeletal protein; BDNF, brain derived neurotrophic factor; CMS, chronic mild stress; DG, dentate gyrus; FST, forced swimming test; IEG, immediate early gene; PBS, phosphate-buffered saline; SSC, saline sodium citrate buffer; SVP, synaptic vesicle protein; VGLUT1, vesicular glutamate transporter 1; WT, wild type. AbstractDepression has been linked to failure in synaptic plasticity originating from environmental and/or genetic risk factors. The chronic mild stress model regulates the expression of synaptic markers of neurotransmitter function and associated depressive-like behaviour. Moreover, mice heterozygous for the synaptic vesicle protein 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, mechanisms of failure in synaptic plasticity, common to stress and impaired glutamate function. First, we show that chronic mild stress induced a transient decrease of different plasticity markers (VGLUT1, synapsin 1, sinaptophysin, rab3A and activity regulated cytoskeletal protein -Arc) but a long-lasting decrease of the brain derived neurotrophic factor as well as depressive-like behaviour. The immediate early gene Arc was also down-regulated in VGLUT1+/) heterozygous mice. In contrast, an opposite regulation of synapsin 1 was observed. Finally, both models showed a marked increase of cortical Arc response to novelty. Increased Arc response to novelty could be suggested as a molecular mechanism underlying failure to adapt to environmental changes, common to chronic stress and altered glutamate function. Further studies should investigate whether these changes are associated to depressivelike behaviour both in animal models and in depressed patients.

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

“…The principal finding of the current study is that administration of a VGLUT1-targeting lentiviral shRNA vector into the dorsal hippocampus of Targeting whole-brain VGLUT1 expression using conventional gene knockout strategies results in a 35-41% decrease in transporter levels in heterozygous animals (Tordera et al, 2007;Garcia-Garcia et al, 2009). These mice exhibit anxiety and a 'depressive-like' phenotype accompanied by deficits in working, social, and visual recognition memory and impaired PPI, reversal learning, fear extinction, and hippocampal long-term potentiation (Tordera et al, 2007;Garcia-Garcia et al, 2009;Balschun et al, 2010;Elizalde et al, 2010;Inta et al, 2012;Callaerts-Vegh et al, 2013). The latter is consistent with the fact that VGLUT1 localizes to synapses with low release probability (that exhibit long-term potentiation), whereas VGLUT2 localizes to synapses with high release probability (that exhibit longterm depression; Varoqui et al, 2002).…”

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

“…If major depression is due to lack of reward, the analysis of molecular profiles in the nucleus accumbens from CUMS‐induced depression and resilience should help to figure out the role of the nucleus accumbens in major depression and resilience based on molecules analyzed. The alternations of certain genes have not been observed in previous analyses (Bai et al, 2014; Elizalde et al, 2010; Li et al, 2013; Liu et al, 2015; Moreau, Bruse, David‐Rus, Buyske, & Brzustowicz, 2011; Rajkowska et al, 2015; Smalheiser et al, 2012, 2011, 2014), including Cckar , Tshr , Kcnj5 , Alox12 , Slc17a6 , Per2 , Rtn4r , and Nrn1 . These genes in the nucleus accumbens may be newly working for major depression or resilience.…”

Chronic Variable Stress Alters Inflammatory and Cholinergic Parameters in Hippocampus of Rats

“…CVS chronic variable stress The CVS procedure was developed as an animal model of depression that presents three important characteristics: the inducing conditions are relatively realistic, the focus of the model is a core symptom of depression, anhedonia, and the protracted time course of the model is suitable for investigating the effects of chronic drug treatments [31]. A series of publications have reported that the CVS procedure causes decreased intake of sucrose solutions (or pellets) [32][33][34][35], impairments in other measures of hedonic reactivity such as place preference conditioning [36,37] and brain stimulation reward [38,39], decreased sexual and aggressive behaviors [40,41] and self-care [42][43][44], in addition to changes in sleep architecture [39,45]. Moreover, these behavioral changes are reversed by chronic treatment with all classes of clinically-effective antidepressant drugs, but not by drugs known to be ineffective as antidepressants.…”