The hippocampus is required for encoding spatial information. Little is known however, about how different attributes of learning are related to different types of synaptic plasticity. Here, we investigated the association between long-term depression (LTD) and long-term potentiation, both cellular models for learning, and novelty exploration. We found that exploration of a new environment containing unfamiliar objects and/or familiar objects in new locations facilitated LTD, whereas exploration of the new environment itself, in the absence of objects, impaired LTD. Furthermore, we found this phenomenon to be modulated by 5-hydroxytryptamine 4 receptor activation. In contrast, long-term potentiation was facilitated by exploration of an empty novel environment, but simultaneous object exploration caused depotentiation. We also found that no further LTD could be induced. These findings support a decisive role for LTD in the acquisition of object–place configuration and consolidate its candidacy as a learning mechanism.