Recent hypotheses propose that one prerequisite to obtain a rapid antidepressant (AD) effect would reside in processes of synaptic reinforcement occurring within the dentate gyrus (DG) of the hippocampus independently from neurogenesis. However, to date no relationship has been established between an increased DG synaptic plasticity, and rapid AD-like action. To the best of our knowledge, this study shows for the first time that inducing a long-term potentiation (LTP) within the DG by stimulating the perforant pathway (PP) is sufficient to induce such effects. Thus, Sprague-Dawley rats having undergone a successful LTP displayed a significant reduction of immobility when passed acutely 3 days thereafter in the forced swimming test (FST). Further, in a longitudinal paradigm using the pseudo-depressed Wistar-Kyoto rat strain, LTP elicited a decrease of FST immobility after only 2 days, whereas the AD desipramine was not effective before 16 days. In both models, the influence of LTP was transient, as it was no more observed after 8-9 days. No effects were observed on the locomotor activity or on anxiety-related behavior. Theta-burst stimulation of a brain region anatomically adjacent to the PP remained ineffective in the FST. Immunoreactivity of DG cells for phosphorylated histone H3 and doublecortin were not modified three days after LTP, indicating a lack of effect on both cell proliferation and neurogenesis. Finally, depleting brain serotonin contents reduced the success rate of LTP but did not affect its subsequent AD-like effects. These results confirm the 'plastic DG' theory of rapid AD efficacy. Beyond, they point out stimulations of the entorhinal cortex, from which the PP originates, as putative new approaches in AD research.Molecular Psychiatry advance online publication, 9 May 2017; doi:10.1038/mp.2017.94.