The human hippocampus is critical for learning and memory. In rodents, hippocampal pyramidal neurons fire in a location-specific manner, forming relational representations of environmental cues. The importance of glutamatergic systems in learning and in hippocampal neural synaptic plasticity has been shown. However, the role of dopaminergic systems in the response of hippocampal neural plasticity to novel and familiar spatial stimuli remains unclear. To clarify this important issue, we recorded hippocampal neurons from dopamine D(1) receptor knock-out (D1R-KO) mice and their wild-type (WT) littermates under the manipulation of distinct spatial cues in a familiar and a novel environment. Here we report that in WT mice, the majority of place cells quickly responded to the manipulations of distal and proximal cues in both familiar and novel environments. In contrast, the influence of distal cues on spatial firing in D1R-KO mice was abolished. In the D1R-KO mice, the influence of proximal cues was facilitated in a familiar environment, and in a novel environment most of the place cells were less likely to respond to changes of spatial cues. Our results demonstrate that hippocampal neurons in mice can rapidly and flexibly encode information about space from both distal and proximal cues to cipher a novel environment. This ability is necessary for many types of learning, and lacking D1R can radically alter this learning-related neural activity. We propose that D1R is crucially implicated in encoding spatial information in novel environments, and influences the plasticity of hippocampal representations, which is important in spatial learning and memory.