AbstractNeur1 and Neur2, mouse homologs of the Drosophila neur gene, consist of two neuralized homology repeat domains and a RING domain. Both Neur1 and Neur2 are 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 of Neur1 enhances hippocampus‐dependent memory, whereas the role of Neur2 remains largely unknown. Here, we aimed to elucidate the respective roles of Neur1 and Neur2 in hippocampus‐dependent memory using three lines of genetically modified mice: Neur1 knock‐out, Neur2 knock‐out, and Neur1 and Neur2 double knock‐out (D‐KO). Our results showed that spatial memory was impaired when both Neur1 and Neur2 were deleted, but not in the individual knock‐out of either Neur1 or Neur2. 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 that Neur1 and Neur2 are crucially involved in hippocampus‐dependent spatial memory and synaptic plasticity.