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

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 cognitivefunction remains unclear. Here, we demonstrate that CRTH2 is involved in cognitivefunction using a well-established animal model of cognitivedysfunction induced by MK-801, an N-methyl-d-aspartate receptor antagonist. Genetic deletion and pharmacological inhibition of CRTH2 suppressed MK-801-induced cognitivedysfunction. Pharmacological inhibition of cyclooxygenase-1, a rate-limiting enzyme in PG synthesis, also suppressed MK-801-induced cognitivedysfunction. 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 cognitivedysfunction and neuronal activity regulation in the PVN. Furthermore, genetic associationstudies suggest that CRTH2 is weakly associated with cognitivefunction in humans. Our study provides evidence that PGD2-CRTH2 signaling is involved in cognitivefunction and may represent a potential therapeutic target for cognitivedysfunction in patients with psychiatric disorders.