CD157, known as bone marrow stromal cell antigen-1, is a glycosylphosphatidylinositol-anchored ADP-ribosyl cyclase supporting survival and function of B lymphocytes and hematopoietic or intestinal stem cells. It was first reported in 2009 that CD157 is a risk locus in Parkinson's disease. To analyze the role of CD157 in the nervous system and how this molecule contributes to Parkinson's disease progression, we used CD157 knockout (KO) mice. CD157 KO mice show no coordinate motor dysfunction, but very low daily activity. CD157 KO adult male mice exhibited anxiety-related behavior, social avoidance, severe fear and depression-like behavior, compared with wild-type mice. This depression-like behavior was rescued by three types of anti-depressants. These results demonstrate a critical role for CD157 in neuropsychiatric functions, which makes it a potential new target for psychiatric symptoms.