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.