Abstract
Injection of nanomolar amounts of prostaglandin D2 (PGD2) into the rat brain has dose and time-dependent somnogenic effects, and the PGD2-induced sleep is indistinguishable from physiologic sleep. Sleep-inducing PGD2 is produced in the brain by lipocalin-type PGD2 synthase (LPGDS). Three potential intracranial sources of LPGDS have been identified: oligodendrocytes, choroid plexus, and leptomeninges. We aimed at the identification of the site of synthesis of somnogenic PGD2 and therefore, generated a transgenic mouse line with the LPGDS gene amenable to conditional deletion using Cre recombinase (flox-LPGDS mouse). To identify the cell type responsible for producing somnogenic PGD2, we engineered animals lacking LPGDS expression specifically in oligodendrocytes (OD-LPGDS KO), choroid plexus (CP-LPGDS KO), or leptomeninges (LM-LPGDS KO). We measured prostaglandins and LPGDS concentrations together with PGD synthase activity in the brain of these mice. While the LPGDS amount and PGD synthase activity were drastically reduced in the OD- and LM-LPGDS KO mice, they were unchanged in the CP-LPGDS KO mice compared with control animals. We then recorded electroencephalograms, electromyograms, and locomotor activity to measure sleep in 10-week-old mice with specific knockdown of LPGDS in each of the three targets. Using selenium tetrachloride, a specific PGDS inhibitor, we demonstrated that sleep is inhibited in OD-LPGDS and CP-LPGDS KO mice, but not in the LM-LPGDS KO mice. We concluded that somnogenic PGD2 is produced primarily by the leptomeninges, and not by oligodendrocytes or choroid plexus.
Highlights
In 1982, it was discovered that microinjecting prostaglandin (PG) D2 into the preoptic area of conscious rats induces sleep (Ueno et al, 1982)
KO mice for the choroid plexus (CP), OD, and LM based on a mouse line in which the lipocalin-type prostaglandin D2 (PGD2) synthase (LPGDS) gene is flanked by loxP sites in intron 1 and 6 and is amenable to conditional deletion by Cre recombinase (Supplementary Figure S1) (Kaneko et al, 2012)
To generate CP-LPGDS KO mice, we infused 50 μL of adeno-associated virus (AAV)-Cre, serotype 5 (AAV5Cre), into the lateral ventricle of adult animals and 3 weeks later immunostaining confirmed the selective absence of LPGDS in the CP (Figures 1I–L)
Summary
In 1982, it was discovered that microinjecting prostaglandin (PG) D2 into the preoptic area of conscious rats induces sleep (Ueno et al, 1982). Other substances that induce sleep are cytokines (Krueger et al, 2011), adenosine (Porkka-Heiskanen et al, 1997; McCarley, 2007; Huang et al, 2011; PorkkaHeiskanen and Kalinchuk, 2011), anandamide (Garcia-Garcia et al, 2009), and peptides such as urotensin II (Huitron-Resendiz et al, 2005). These studies independently postulated that prolonged periods of wakefulness can lead to an accumulation of hypothetical endogenous substances that induce sleep. Elevated PGD2 levels are found in diseases with sleep alterations such as mastocytosis and African trypanosomiasis (Roberts et al, 1980; Pentreath et al, 1990)
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