title: CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice.
abstract: Depression is a complex neuropsychiatric disorder with an unclear molecular etiology. Inflammatory cytokines and molecular intermediates (including prostaglandins) are suggested to be involved in depression; however, the roles of prostaglandins and their respective receptors are largely unknown in depression. Using genetic and pharmacological approaches, we show here that chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a second receptor for prostaglandin D2 (PGD2), mediates depression-related behavior in mice. CRTH2-deficient (CRTH2(-/-)) mice showed antidepressant-like activity in a chronic corticosterone treatment-induced depression. Consistent with this observation, the pharmacological inhibition of CRTH2 via the clinically available drug ramatroban also rescued abnormal social interaction and depression-related behavior in well-established models, including chronic corticosterone-, lipopolysaccharide-, and tumor-induced pathologically relevant depression models. Importantly, chronic stress via corticosterone treatment increased mRNA levels in PGD2-producing enzymes, such as cyclooxygenase-2 and lipocalin-type PGD2 synthase, in the brain. Furthermore, the activity of the hippocampal noradrenergic system but not the dopaminergic or serotonergic systems was increased in CRTH2(-/-) mice. Together with the observation that untreated CRTH2(-/-) mice showed antidepressant-like activity in the forced swim test, these results provide evidence that central CRTH2-mediated signaling is critically involved in depression-related behavior.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Onaka
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: shintani@phs.osaka-u.ac.jp.
authors.forename: Norihito
authors.initials: N
authors.lastname: Shintani
authors.affiliation: iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Haba
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Semel Institute for Neuroscience and Human Behavior, Intellectual Development and Disabilities Research Center, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hyper
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kanoh
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hayata-Takano
authors.affiliation: Department of Advanced Medicine and Development, Bio Medical Laboratories, Inc., 1361-1 Matoba, Kawagoe, Saitama 350-1101, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Department of Advanced Medicine and Development, Bio Medical Laboratories, Inc., 1361-1 Matoba, Kawagoe, Saitama 350-1101, Japan.
authors.forename: Kin-Ya
authors.initials: KY
authors.lastname: Nagata
authors.affiliation: Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Psychiatry, Graduate School of Medicine, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, Intellectual Development and Disabilities Research Center, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Waschek
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasai
authors.affiliation: iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nagayasu
authors.affiliation: Pharmaceutical Sciences, Hyogo University of Health Science, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: hasimoto@phs.osaka-u.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D002908:Chronic Disease; D003345:Corticosterone; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003866:Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D054834:Lipocalins / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C495402:Adcyap1 protein, mouse; D002227:Carbazoles; D002491:Central Nervous System Agents; D054834:Lipocalins; D008070:Lipopolysaccharides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; C063119:ramatroban; D003345:Corticosterone; D009638:Norepinephrine; C036293:prostaglandin D2 receptor
keywords: CRTH2; Depression; Depression-related behavior; Noradrenaline; Prostaglandin D2