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  • It has been reported that NMDA receptor hypofunction


    It has been reported that NMDA receptor hypofunction upregulates the expression of immediate early genes in several Varenicline Tartrate synthesis regions [39], [40]. Consistent with this finding, we demonstrated that MK-801 increased the number of c-Fos-positive cells in the PVN and PC/RS (Fig. 5). Importantly, the MK-801-induced increase in the number of c-Fos-positive cells was selectively eliminated in the PVN of the CRTH2−/− mice (Fig. 5). We have previously demonstrated that CRTH2 also regulates LPS-induced emotional changes in the PVN [16]. Furthermore, CRTH2 deficiency did not affect c-Fos expression in the hippocampus and interconnected PFC (Fig. 5), which are implicated in the performance of the NORT [41]. These findings indicate that CRTH2 likely functions selectively to some extent in the PVN. Currently, the downstream intracellular signaling of CRTH2 in the PVN is unclear. We have previously demonstrated that CRTH2 signaling enhances the phosphorylation of MAP kinase in PC12 cells [47]. Given that c-Fos is induced by the ERK/MAP kinase pathway [48], ERK activation downstream of CRTH2 may be involved in the induction of c-Fos expression. The genetic association analysis indicated that CRTH2 haplotypes (SNP1 (rs575042)-SNP2 (rs4939469), SNP2-SNP3 (rs634681) and SNP1-SNP2-SNP3) were weakly associated with schizophrenia (Table 2), and each SNP in the CRTH2 gene was associated with human cognitive function, as demonstrated by the WCST, the WMS-R and the WAIS-III (Table 3). Importantly, a significant interaction between genotype and diagnosis was identified for SNP2 in Attention/Concentration in the WMS-R (Table 3). Using CRTH2−/− mice, we demonstrated that CRTH2-mediated signaling is involved in MK-801-induced cognitive dysfunction in the NORT (Fig. 3), a commonly used animal model of psychiatric disorders [19]. These findings are mutually supportive and indicate that CRTH2-mediated signaling may be related to human cognitive dysfunction in schizophrenia. However, considerable caution is necessary in the interpretation of these results because there are marked differences in memory systems across species [44]. Previous studies have reported that there is a significant association between SNP4 (rs11571288) of the CRTH2 gene and an increased risk for a specific IgE to food allergens in German children [49]. Furthermore, the haplotype SNP4-SNP5 (rs545659) is related to CRTH2 mRNA stability [50]. Currently, the functional consequence of each SNP is largely unknown. Future studies, particularly an analysis of the functional consequence of each SNP, are necessary to elucidate the role of CRTH2 in human cognitive function. In conclusion, our current study provides evidence suggesting that COX-1-PGD2-CRTH2 signaling is involved in cognitive function. The genetic deletion or pharmacological inhibition of CRTH2 ameliorates MK-801-induced cognitive dysfunction; thus, COX-1-PGD2-CRTH2 signaling may represent a potential therapeutic target for cognitive dysfunction in patients with psychiatric disorders.
    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 in Japan (MEXT).
    Introduction Depression is a complex neuropsychiatric disorder with core symptoms of depressed mood, anhedonia, irritability, and abnormalities in sleep and appetite [1]. Approximately, 15% of the population will experience depression at some point during their lifetime, and depression is associated with high morbidity and mortality [2]. Despite its high prevalence and socioeconomic burden, little is known about the etiology of depression. Accordingly, the conventional treatment of depression with antidepressant medications is effective in only approximately 50% of patients [3]. Therefore, establishing the molecular pathology underlying depression is important for improving treatment.