Neur1andNeur2, mouse homologs of theDrosophila neurgene, consist of two neuralized homology repeat domains and a RING domain. BothNeur1andNeur2are expressed in the whole adult brain and encode E3 ubiquitin ligases, which play a crucial role in the Notch signaling pathways. A previous study reported that overexpression ofNeur1enhances hippocampus-dependent memory, whereas the role ofNeur2remains largely unknown. Here, we aimed to elucidate the respective roles ofNeur1andNeur2in hippocampus-dependent memory using three lines of genetically modified mice:Neur1knock-out,Neur2knock-out, andNeur1andNeur2double knock-out (D-KO). Our results showed that spatial memory was impaired when bothNeur1andNeur2were deleted, but not in the individual knock-out of eitherNeur1orNeur2. In addition, basal synaptic properties estimated by input-output relationships and paired-pulse facilitation did not change, but a form of long-term potentiation that requires protein synthesis was specifically impaired in the D-KO mice. These results collectively suggest thatNeur1andNeur2are crucially involved in hippocampus-dependent spatial memory and synaptic plasticity.