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Previous research shows Ouabain (OUA) to bind Na, K-ATPase, thereby triggering a number of signaling pathways, including the transcription factors NFκB and CREB. These transcription factors play a key role in the regulation of BDNF and WNT-β-catenin signaling cascades, which are involved in neuroprotection and memory regulation. This study investigated the effects of OUA (10 nM) in the modulation of the principal signaling pathways involved in morphological plasticity and memory formation in the hippocampus of adult rats. The results show intrahippocampal injection of OUA 10 nM to activate the Wnt/β-Catenin signaling pathway and to increase CREB/BDNF and NFκB levels. These effects contribute to important changes in the cellular microenvironment, resulting in enhanced levels of dendritic branching in hippocampal neurons, in association with an improvement in spatial reference memory and the inhibition of long-term memory extinction.Intrahippocampal injection of OUA 10 nM increases NFκB activation in adult rats.OUA increase BDNF expression and CREB activity in rat hippocampus.After 24 h OUA infusion, Wnt-β-Catenin signaling pathway is more active in CA1 neurons.10 nM OUA treatment lead increased CA1 and DG dendritic branching and improved spatial reference memory.OUA improve spatial reference memory.