The susceptibility to chronic social isolation (CSIS) is associated with development of major depression (MD). Recent studies relate MD with altered expression of synaptic proteins in specific brain regions, whereby some individuals exposed to the stressors are resistant to the stress. To explore the neurobiological underpinnings and identify candidate biomarkers for MD, a comparative proteomic approach was used to map hippocampal synaptic protein alterations of rats exposed to 6 weeks of CSIS, an animal model of depression. This model generates two stress-response phenotypes, reflecting CSIS-sensitive (depressive-like behaviour) and CSIS-resilience, assessed by sucrose preference test. Our aim was to characterize the synaptoproteome changes representative of potential long-term changes in protein expression underlying susceptibility or resilience to stress.