Elsevier

Behavioural Brain Research

Volume 314, 1 November 2016, Pages 77-86
Behavioural Brain Research

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

https://doi.org/10.1016/j.bbr.2016.07.050Get rights and content

Highlights

  • Genetic deletion of CRTH2 suppressed MK-801-induced cognitive dysfunction.

  • Inhibition of CRTH2 by ramatroban suppressed MK-801-induced cognitive dysfunction.

  • Inhibition of COX-1 by SC-560 suppressed MK-801-induced cognitive dysfunction.

  • MK-801-induced increase in c-Fos expression in the PVN was abolished in CRTH2−/− mice.

  • PGD2-CRTH2 signaling is involved in MK-801-induced cognitive dysfunction.

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.

Introduction

Several psychiatric and neurological disorders are associated with cognitive dysfunction, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorders, bipolar disorder, depression and schizophrenia [1], [2], [3]. Many pathological factors, such as stress and neuroinflammation, also contribute to cognitive dysfunction [4], [5]. Therefore, it is important to elucidate the molecular mechanisms that underlie cognitive dysfunction to develop therapies for various psychiatric and neurological disorders.

Neuroinflammation plays an important role in cognitive dysfunction [5]. Inflammatory cytokines, such as interleukin-1β and tumor necrosis factor α, contribute to cognitive dysfunction [6], [7]. Cyclooxygenase (COX), a rate-limiting enzyme in prostanoid synthesis, also plays a role in neuroinflammation-mediated cognitive dysfunction [8]. Previous studies have demonstrated that COX activity is increased in the platelets of patients with schizophrenia [9] and that COX-2 is upregulated in the hippocampus of Alzheimer’s disease patients [10]. Therefore, the COX pathway and its downstream signaling molecule prostanoid have emerged as main players involved in cognitive dysfunction in pathological conditions. Prostanoids, such as prostaglandins (PGs) (PGD2, PGE2, PGF and PGI2) and thromboxane A2, which are synthesized through the sequential actions of COX and their respective synthases, function through their cognate G-protein-coupled receptors [8], [11]. Therefore, to fully understand the roles of prostanoid signaling in neuroinflammation-mediated cognitive dysfunction, it is important to dissect the role of each prostanoid and its receptor in pathological conditions. To date, there is limited evidence regarding the specific prostanoids and their receptors that are related to cognitive dysfunction in pathological conditions.

Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) is a second PGD2 receptor with roles in peripheral tissue. CRTH2-mediated signaling promotes leukocyte migration [12], [13] and exacerbates allergic rhinitis [14], [15]. In addition to its peripheral roles, we have recently demonstrated that CRTH2-mediated signaling mediates emotional impairment in a lipopolysaccharide (LPS)- and tumor-induced sickness behavior model, and depression-related behavior in animal models of human depression [16], [17]. In addition, we have demonstrated that the blockade of CRTH2-mediated signaling suppresses LPS- and tumor-induced decreases in novel object investigation behavior, which indicates a loss of interest rather than a decline in cognition [16]. These findings suggest that CRTH2-mediated signaling plays an important role in emotional behavior and have led us to investigate the potential role of CRTH2-mediated signaling in other higher brain functions, such as cognition.

N-methyl-d-aspartate (NMDA) receptor antagonists, such as MK-801 and phencyclidine, induce cognitive dysfunction in both mice and humans [18]. In addition, antipsychotic drugs ameliorate MK-801-induced cognitive dysfunction; therefore, the acute application of MK-801 can be used as an animal model of psychiatric disorders [19]. In the present study, we investigated the effects of genetic deletion or pharmacological inhibition of CRTH2 on MK-801-induced cognitive dysfunction and provide the first report that CRTH2-mediated signaling is involved in MK-801-induced cognitive dysfunction. In addition to the role of CRTH2 in cognition in mice, we further investigated the potential involvement of CRTH2 in human cognitive function via an association study between genetic polymorphisms of CRTH2 and cognitive function or schizophrenia. We found that single nucleotide polymorphisms (SNPs) in the CRTH2 gene are weakly associated with human cognitive function and schizophrenia.

Section snippets

Animals

All animal care and handling procedures were approved by the Animal Care and Use Committee of the Graduate School of Pharmaceutical Sciences at Osaka University. The generation of CRTH2−/− mice using gene targeting has been previously reported [20]. Male BALB/c (BALB/cCrSlc) mice (8 week old) were purchased from Shimizu Laboratories Supplies (Kyoto, Japan) [20] and used for the ramatroban study; ramatroban is a clinically available antagonist of CRTH2 and the thromboxane A2 receptor [13]. Male

Normal cognitive function in naïve CRTH2 knockout (CRTH2−/−) mice

We initially performed behavioral tests to determine the role of CRTH2 in cognitive function using CRTH2−/− mice. There were no genotypic effects on exploratory preference in the NORT, the percentage of alternations in the Y-maze test, the latency to fall in the rota-rod test or the freezing behavior in the fear-conditioning test (Fig. 1). These findings suggest that the CRTH2−/− mice had normal baseline spatial memory, working memory, motor learning and emotional memory.

Application of 0.1 mg/kg of MK-801 did not affect locomotor activity in CRTH2−/− mice

Changes in locomotor

Discussion

Previous studies have demonstrated that prostanoid signaling in the brain is involved in cognitive function [8]; however, there is little evidence to indicate that the PGD2-CRTH2 signaling pathway is involved in cognitive function. The present study demonstrated that the genetic deletion and pharmacological inhibition of CRTH2 abolishes MK-801-induced cognitive dysfunction in the NORT. We also demonstrated that the inhibition of COX-1, but not COX-2, eliminates MK-801-induced cognitive

Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI), a Research Fellowship for Young Scientists (Y.O.), a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) and the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603; H. Hashimoto) from the Japan Society for the Promotion of Science (JSPS) or the Ministry of Education, Culture, Sports, Science and Technology

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    These authors have contributed equally to this work.

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