Objective To study the function of LSD1 in the development of neurons and the influence of LSD1 on mood and memory-related behavior in mice. Methods The LSD1^(flox/flox) transgenic mice were crossed with Nestin-cre^(Tg) transgenic mice, using Cre-LoxP recombination system, to generate LSD1 conditional knockout of neural stem cell (LSD1-CKO) mice, LSD1^(flox/flox) Nestin-cre^(Tg) mice, and LSD1^(flox/flox) mice as control. The neuron proliferation in LSD1-CKO mice was further detected by immunofluorescence staining. At the same time, the mood and memory-related behavior of LSD1-CKO mice were examined using several methods:sucrose preference test (SPT), forced swimming test (FST) and novel-object recognition (NOR) assay. Results In the LSD1 brain-specific CKO mice, the neuron proliferation rate in the hippocampus was significantly reduced (P=0.023), the preference for sucrose was reduced (P=0.0075), immobility duration during the forced swimming test was increased (P<0.05), and LSD1-CKO mice also exhibits memory-decline (P=0.0019) during the novel-object recognition test. Conclusions Depletion of LSD1 in mouse brain neural stem cells leads to significant reduction of the neuron proliferation in the hippocampus. LSD1-CKO mice show more negative emotions and memory impairment.