EP4 receptor-associated protein (EPRAP) is a newly identified molecule that regulates macrophage activation. We recently demonstrated the presence of EPRAP in the mice brain; however, little is known about the function of EPRAP in this tissue. Therefore, we investigated the role of EPRAP in behavior and emotion using behavioral analysis in mice. In this study, we subjected EPRAP-deficient (KO) mice and wild-type C57BL/6 (WT) mice to a battery of behavioral tests. EPRAP-KO mice tended to have shorter latencies to fall in the wire hang test, but had normal neuromuscular strength. EPRAP-KO mice exhibited elevated startle responses and reduced pre-pulse inhibition. Compared with WT mice, EPRAP-KO mice increased depression-like behavior in the forced swim test. These abnormal behaviors partially mimic symptoms of depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia. Methylphenidate administration increased locomotor activity less in EPRAP-KO mice than in WT mice. Finally, levels of norepinephrine were reduced in the EPRAP-KO mouser brain. These behavioral abnormalities in EPRAP-KO mice may result from the dysfunction of monoamines, in particular, norepinephrine. Our results suggest that EPRAP participates in the pathogenesis of various behavioral disorders. (C) 2017 Elsevier Inc. All rights reserved.