We previously reported a long-term potentiation (LTP)-like facilitation in vivo, known as synaptic plasticity, through GABA_A receptor blockade by bicuculline in the mouse dentate gyrus, and protein expression profiles in the hippocampus of mice overexpressing human APP with the E693∆ mutation (APP_OSK-Tg) as Alzheimer‘s disease model showing impaired synaptic plasticity. In this study, we investigated whether bicuculline ameliorated impaired synaptic plasticity, and analyzed its mechanism involved with this improvement by proteome analysis. Electrophysiological study showed that the LTP-like facilitation in vivo induced by bicuculline was significantly greater than impaired tetanic LTP in APP_OSK-Tg mice, which was improved by bicuculline. Proteomic analysis showed that significant changes 8 h after bicuculline application in expression of 11 (9 up- and 2 downregulated) proteins in the hippocampus of APP_OSK-Tg mice. The identified proteins could be functionally classified as chaperome, cytoskeletal protein, energy metabolism, metabolism, neuronal development, and synaptic component. Thus, these results show that bicuculline improves impaired tetanic LTP in the dentate gyrus and changes the expression of proteins in the hippocampus of APP_OSK-Tg mice. We propose that the improvement of impaired synaptic plasticity through GABA_A receptor blockade could be mediated by alterations in expression levels of these proteins.