Dominant localization of prostaglandin D receptors on arachnoid trabecular cells in mouse basal forebrain and their involvement in the regulation of non-rapid eye movement sleep

Abstract

Infusion of prostaglandin (PG) D2 into the lateral ventricle of the brain induced an increase in the amount of non-rapid eye movement sleep in wild-type (WT) mice but not in mice deficient in the PGD receptor (DP). Immunofluorescence staining of WT mouse brain revealed that DP immunoreactivity was dominantly localized in the leptomeninges (LM) of the basal forebrain but that PGD synthase immunoreactivity was widely distributed in the LM of the entire brain. Electron microscopic observation indicated that DPimmunoreactive particles were predominantly located on the plasma membranes of arachnoid trabecular cells of the LM. The region with the highest DP immunoreactivity was clearly defined as bilateral wings in the LM of the basal forebrain located lateral to the optic chiasm in the proximity of the ventrolateral preoptic area, one of the putative sleep centers, and the tuberomammillary nucleus, one of the putative wake centers. The LM of this region contained DP mRNA 70-fold higher than that in the cortex as judged from the results of quantitative reverse transcription-PCR. PGD2 infusion into the subarachnoid space of this region increased the extracellular adenosine level more than 2-fold in WT mice but not in the DP-deficient mice. These results indicate that DPs in the arachnoid trabecular cells of the basal forebrain mediate an increase in the extracellular adenosine level and sleep induction by PGD2. P rostaglandin (PG) D 2 is a potent endogenous sleeppromoting substance in monkeys and rats, and its somnogenic mechanism is the best characterized among those of various sleep-inducing substances (reviewed in ref. 1). In brief, PGD 2 infused into the subarachnoid space underlying the rostral basal forebrain was effective in inducing sleep but not when infused into most parts of the brain parenchyma of rats (2). The amount of PGD 2 -induced sleep was reduced by pretreatment with KF17837, the specific adenosine A 2A receptor antagonist, in a dose-dependent manner (3). Administration of CGS21680, a selective A 2A receptor agonist, into the subarachnoid space induced sleep (4), suggesting that PGD 2 -induced sleep is mediated by adenosine through the adenosine A 2A receptor system. Furthermore, PGD 2 infusion significantly increased Fos expression in the leptomeninges (LM) and neurons within the ventrolateral preoptic area, one of the putative sleep centers, and simultaneously decreased Fos expression in the tuberomammillary nucleus, one of the putative wake centers (5).PGD synthase (PGDS) is mainly produced in the LM and choroid plexus of the brain (6) and secreted into the cerebrospinal fluid (CSF) to become ␤-trace, a major CSF protein (reviewed in ref. 7). We recently reported that human PGDSoverexpressing transgenic mice exhibited excessive amounts of non-rapid eye movement (NREM) sleep, but not rapid eye movement (REM) sleep, in response to the noxious stimulus by tail clipping, coupled with a significant increase in the PGD 2 content in the brain (8). Therefore, PGD 2 , PGDS, and the PGDS gene are considered...

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

“…PGD 2 is produced as a major PG in the brain of various mammals including humans by lipocalin-type PGD synthase (L-PGDS; Qu et al, 2006), which is dominantly present in the arachnoid membrane surrounding the brain, the choroid plexus in the ventricles, and oligodendrocytes in the brain parenchyma (Beuckmann et al, 2000). From its sites of synthesis, it is secreted into the CSF and bound to DP receptors (Qu et al, 2006), which are also present in the arachnoid membrane yet limited to that of the rostral basal forebrain (Mizoguchi et al, 2001). The binding of PGD 2 to DP receptors on the meninges is followed by an increase in the extracellular concentration of adenosine (Mizoguchi et al, 2001), which transfers the somnogenic signal from the meningeal membrane into the brain parenchyma including the sleep and wake centers in the hypothalamus (Scammell et al, 1998;.…”

“…From its sites of synthesis, it is secreted into the CSF and bound to DP receptors (Qu et al, 2006), which are also present in the arachnoid membrane yet limited to that of the rostral basal forebrain (Mizoguchi et al, 2001). The binding of PGD 2 to DP receptors on the meninges is followed by an increase in the extracellular concentration of adenosine (Mizoguchi et al, 2001), which transfers the somnogenic signal from the meningeal membrane into the brain parenchyma including the sleep and wake centers in the hypothalamus (Scammell et al, 1998;.…”

Comprehensive expression analysis of a rat depression model

“…32 This enzyme has recently been implicated in the regulation of nonrapid eye movement (NREM). 33 Sleep disturbance is a typical symptom of human depression. Examination of sleep parameters in LH rats, particularly the NREM period, would therefore be of interest.…”

Pivotal roles of the parasite PGD2 synthase and of the host D prostanoid receptor 1 in schistosome immune evasion

“…PGD 2 , a major metabolite of arachidonic acid, has various physiological activities in mammals such as promotion of sleep, nerve cell function, hormone release, bronchoconstriction and vasodilatation [1,2]. In addition, PGD 2 also possesses effector functions during inflammation.…”