Behavioral abnormalities and reduced norepinephrine in EP4 receptor-associated protein (EPRAP)-deficient mice.
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 mouse 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.
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan; Research Fellow of Japan Society for the Promotion of Science, Kojimachi Business Center Building, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan.
Risako
R
Fujikawa
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
Sei
S
Higuchi
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
Taichi
T
Ikedo
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
Manabu
M
Nagata
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
Kosuke
K
Hayashi
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
Tao
T
Yang
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
Takeshi
T
Miyata
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
Masayuki
M
Yokode
Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan. Electronic address: mminami@kuhp.kyoto-u.ac.jp.
Manabu
M
Minami
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001522:Behavior, Animal; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics; D003863:Depression / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism*; D065808:Prepulse Inhibition / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism
D018797:Cell Cycle Proteins; C506176:Fem1a protein, mouse; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine
Brain; Depression; Glia; Mental disorder; Norepinephrine