Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction

Yusuke Onaka; Norihito Shintani; Takanobu Nakazawa; Takuya Kanoh; Yukio Ago; Toshio Matsuda; Ryota Hashimoto; Kazutaka Ohi; Hiroyuki Hirai; Kin-Ya Nagata; Masataka Nakamura; Atsushi Kasai; Atsuko Hayata-Takano; Kazuki Nagayasu; Kazuhiro Takuma; Asao Ogawa; Akemichi Baba; Hitoshi Hashimoto

doi:10.1016/j.bbr.2016.07.050

Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction

Behav Brain Res. 2016 Nov 1:314:77-86. doi: 10.1016/j.bbr.2016.07.050. Epub 2016 Jul 29.

Authors

Yusuke Onaka¹, Norihito Shintani², Takanobu Nakazawa³, Takuya Kanoh⁴, Yukio Ago⁵, Toshio Matsuda⁶, Ryota Hashimoto⁷, Kazutaka Ohi⁸, Hiroyuki Hirai⁹, Kin-Ya Nagata⁹, Masataka Nakamura¹⁰, Atsushi Kasai⁴, Atsuko Hayata-Takano¹¹, Kazuki Nagayasu¹², Kazuhiro Takuma¹³, Asao Ogawa¹⁴, Akemichi Baba¹⁵, Hitoshi Hashimoto¹⁶

Affiliations

¹ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotogecho, Hirakata, Osaka 573-0101, Japan.
² 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.
³ 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; Laboratory of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁴ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁵ 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.
⁶ Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁷ 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, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁸ Department of Psychiatry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁹ Department of Advanced Medicine and Development, Bio Medical Laboratories, Inc., 1361-1 Matoba, Kawagoe, Saitama 350-1101, Japan.
¹⁰ Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
¹¹ 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.
¹² 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.
¹³ Laboratory of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 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.
¹⁴ National Cancer Center Hospital East, Psycho-Oncology Division, Research Center for Innovative Oncology, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
¹⁵ Pharmaceutical Sciences, Hyogo University of Health Science, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
¹⁶ 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; Division of Bioscience, Institute for Datability Science, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: hasimoto@phs.osaka-u.ac.jp.

PMID: 27481693
DOI: 10.1016/j.bbr.2016.07.050

Abstract

Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), which is a second receptor for prostaglandin (PG) D2, is involved in inflammatory responses in peripheral tissue; however, its role in cognitive function remains unclear. Here, we demonstrate that CRTH2 is involved in cognitive function using a well-established animal model of cognitive dysfunction induced by MK-801, an N-methyl-d-aspartate receptor antagonist. Genetic deletion and pharmacological inhibition of CRTH2 suppressed MK-801-induced cognitive dysfunction. Pharmacological inhibition of cyclooxygenase-1, a rate-limiting enzyme in PG synthesis, also suppressed MK-801-induced cognitive dysfunction. Moreover, an MK-801-induced increase in c-Fos expression in the paraventricular nucleus (PVN) was abolished in the CRTH2-deficient mice. Together, these results suggest that PGD2-CRTH2 signaling is involved in both MK-801-induced cognitive dysfunction and neuronal activity regulation in the PVN. Furthermore, genetic association studies suggest that CRTH2 is weakly associated with cognitive function in humans. Our study provides evidence that PGD2-CRTH2 signaling is involved in cognitive function and may represent a potential therapeutic target for cognitive dysfunction in patients with psychiatric disorders.

Keywords: CRTH2; Cognitive dysfunction; MK-801; Prostaglandin D(2).

MeSH terms

Animals
Cognitive Dysfunction / chemically induced
Cognitive Dysfunction / metabolism*
Cognitive Dysfunction / physiopathology
Disease Models, Animal
Dizocilpine Maleate / pharmacology*
Male
Mice, Inbred BALB C
Mice, Knockout
Prostaglandin D2 / metabolism*
Receptors, Immunologic / metabolism*
Receptors, N-Methyl-D-Aspartate / metabolism
Receptors, Prostaglandin / metabolism*
Signal Transduction / drug effects

Substances

Receptors, Immunologic
Receptors, N-Methyl-D-Aspartate
Receptors, Prostaglandin
Dizocilpine Maleate
Prostaglandin D2
prostaglandin D2 receptor