title: Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder.
abstract: An association between serotonin 2A receptor (5-HT2AR), encoded by HTR2A gene, and major depressive disorder (MDD) has been suggested. Here, we combined preclinical and ecological clinical approaches to explore the impact of impaired 5-HT2AR-mediated transmission on MDD or anxio-depressive-like phenotype in mice. Htr2a knock-out mice (Htr2a(-/-)) and wild-type mice were compared for the ability of chronic corticosterone to elicit some anxio-depressive-like phenotype in three behavioral paradigms (elevated plus maze, tail suspension test and splash test). Accordingly, two single nucleotide polymorphisms of the HTR2A gene (rs6314 ie His452Tyr and rs6313 ie 102C/T), which specific allelic variants may decrease 5-HT2AR-mediated transmission (as in Htr2a(-/-)mice), were studied in a sample of 485 Caucasian patients with MDD. In response to chronic corticosterone exposure, Htr2a(-/-) mice displayed more pronounced anxiodepressive-like phenotype than wild-type mice, as shown by a significant higher "emotionality score" (p<0.01). In patients, the C allele of rs6313 was more frequent in depressed patients (p=0.019) and was also associated with a more severe major depressive episode (p=0.03). This translational and ecological study involving constitutive Htr2a(-/-) knock-out mice and related SNPs in depressed patients suggests that a lower neurotransmission at the 5-HT2AR may favor the susceptibility and severity of MDE. It also suggests that specific allelic variants of the rs6313 and rs6314 may reduce 5-HT2AR-mediated transmission.
authors.affiliation: Université Paris Sud XI, INSERM U669, Département de Psychiatrie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, 94275 Le Kremlin Bicêtre, France. Electronic address: annececile.petit@yahoo.fr.
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Petit
authors.affiliation: Université Paris Sud XI, Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Châtenay-Malabry Cedex, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Quesseveur
authors.affiliation: Université Paris Sud XI, INSERM U669, Département de Psychiatrie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, 94275 Le Kremlin Bicêtre, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Gressier
authors.affiliation: Université Paris Sud XI, INSERM U669, Département de Psychiatrie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, 94275 Le Kremlin Bicêtre, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Colle
authors.affiliation: Université Paris Sud XI, Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Châtenay-Malabry Cedex, France.
authors.forename: Denis J
authors.initials: DJ
authors.lastname: David
authors.affiliation: Université Paris Sud XI, Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Châtenay-Malabry Cedex, France.
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.affiliation: Département de Psychiatrie, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Ferreri
authors.affiliation: Hôpital Saint-Louis Lariboisière Fernand Widal, Assistance Publique Hôpitaux de Paris, INSERM U705, CNRS UMR8206, 200 rue du Faubourg Saint Denis, F-75475 Paris Cedex 10, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lépine
authors.affiliation: Université Paris Sud XI, INSERM U669, Département de Biostatistiques, Hôpital Paul Brousse, Assistance Publique Hôpitaux de Paris, 94400 Villejuif, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Falissard
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, F-94275 Le Kremlin Bicêtre, France; Université Paris Sud XI, EA4123, F-92296 Châtenay-Malabry Cedex, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.affiliation: Université Paris Sud XI, Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Châtenay-Malabry Cedex, France. Electronic address: bruno.guiard@u-psud.fr.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
authors.affiliation: Université Paris Sud XI, INSERM U669, Département de Psychiatrie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, 94275 Le Kremlin Bicêtre, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Corruble
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics / Q000503:physiopathology; D003345:Corticosterone; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D003345:Corticosterone
keywords: 5-HT2A receptor; Animal model; Major depression; Single nucleotide polymorphism; Translational study