We suggest that CSDS is not a pure model of depression. Indeed, it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS-induced anhedonia and social avoidance are not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behavior, such as the amygdala, where the glutamatergic mechanism could play a key role.

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Background: Many studies have linked depression to an increase in the excitatory-

This study shows region-specific long-term neurobiological adaptations induced by CMS and residual hippocampal signs after paroxetine treatment. We propose the use of this model to study molecular mechanisms involved in chronic depression and vulnerability for relapse.

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.