Background: Depressive patients show cognitive impairments that are strongly associated with cortisol levels and hippocampus functioning that interact via unknown mechanisms. In addition, a relation between depression and hippocampal synaptic plasticity was described. Methods: In the first experiment, strain-dependent effects of 72-h social isolation on long-term potentiation (LTP) in the CA1 area of the in vitro hippocampus, was determined. Extracellular field excitatory postsynaptic potentials were recorded and a brief high-frequency stimulation (100. Hz, 1. s) was applied and recording resumed after the high frequency stimulation (HFS) for 30. min to determine the effect of HFS.In the second experiment we investigated the effect of 72. h of corticosterone treatment and the involvement of glucocorticoid receptors (GRs) in the effect of 72. h of social isolation on LTP in the CA1 area of hippocampus, in vitro. Results: Genetic background has a major effect on the level of hippocampal LTP impairment in mice following social isolation. Data showed that the potentiation levels in socially housed (SH) A/J mice were significantly higher than the SH C57BL/6J mice (224.88. ±. 16.65, 131.56. ±. 6.25% of the baseline values, t(9). = 2.648, p= 0.026). However, both strains showed depressed induction of potentiation when reared in an isolated environment for 72. h, and no significant difference was recorded between the two (112.88. ±. 16.65%, and 117.91. ±. 3.23% of the baseline values, respectively, t(10) = 0.618, p= 0.551). Social isolation increased corticosterone levels significantly and chronic corticosterone infusion in SH phenocopied the LTP impairments observed in socially isolated mice. Infusion of the GR antagonist RU38486 rescued the LTP-impairments following social isolation. Conclusions: These findings support the notion that increased levels of stress hormone act via the GR on hippocampal functioning and that, in this way, the cognitive deficits in mood disorders may be restored. © 2013 IBRO.