Synaptonuclear signalling pathways have been implicated in long term plasticity events. Nonetheless, their role in regulating cognitive behavior remains to be clarified. Here, we demonstrated that RNF10-mediated synapse-to-nucleus signaling, linking activation of synaptic NMDARs to specific transcriptional programmes in the dorsal CA1, is necessary for cognitive flexibility. In vivo RNF10 downregulation, through gene deletion and silencing, induced, specifically in CA1, alterations of both long-term potentiation and dendritic spines’ structure. At behavioral level, RNF10 downregulation suppressed cognitive flexibility, which is reflected in the impaired ability to disengage from previously acquired contextual, visual, and spatial information and to maintain adaptive goal-directed behavior. Overall, our results identified RNF10 as a key in vivo player necessary for the correct expression of cognitive flexibility.