title: Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains.
abstract: The serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors regulate each other and are associated with schizophrenia. The Roman high- (RHA-I) and the Roman low- (RLA-I) avoidance rat strains present well-differentiated behavioral profiles, with the RHA-I strain emerging as a putative genetic rat model of schizophrenia-related features. The RHA-I strain shows increased 5-HT2Aand decreased mGlu2 receptor binding levels in prefrontal cortex (PFC). Here, we looked for differences in gene expression and transcriptional regulation of these receptors. The striatum (STR) was included in the analysis. 5-HT2A, 5-HT1A, and mGlu2 mRNA and [3H]ketanserin binding levels were measured in brain homogenates. As expected, 5-HT2Abinding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT2Agene expression was unchanged in PFC but significantly decreased in STR. mGlu2 receptor gene expression was significantly decreased in both PFC and STR. No differences were observed for the 5-HT1Areceptor. Chromatin immunoprecipitation assay revealed increased trimethylation of histone 3 at lysine 27 (H3K27me3) at the promoter region of the HTR2A gene in the STR. We further looked at the Akt/GSK3 signaling pathway, a downstream point of convergence of the serotonin and glutamate system, and found increased phosphorylation levels of GSK3β at tyrosine 216 and increased β-catenin levels in the PFC of the RHA-I rats. These results reveal region-specific regulation of the 5-HT2Areceptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg and Frederiksberg Hospitals, Building 11B, 2nd floor, Bispebjerg Bakke 23, 2400, Copenhagen NV, Denmark.
authors.forename: Luna
authors.initials: L
authors.lastname: Fomsgaard
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Moreno
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: de la Fuente Revenga
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg and Frederiksberg Hospitals, Building 11B, 2nd floor, Bispebjerg Bakke 23, 2400, Copenhagen NV, Denmark.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brudek
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg and Frederiksberg Hospitals, Building 11B, 2nd floor, Bispebjerg Bakke 23, 2400, Copenhagen NV, Denmark.
authors.forename: Dea
authors.initials: D
authors.lastname: Adamsen
authors.affiliation: Departamento de Psiquiatria y Medicina Legal, Instituto de Neurociencias, Universidad Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Rio-Alamos
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Saunders
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders Bue
authors.initials: AB
authors.lastname: Klein
authors.affiliation: Departamento de Psiquiatria y Medicina Legal, Instituto de Neurociencias, Universidad Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Oliveras
authors.affiliation: Departamento de Psiquiatria y Medicina Legal, Instituto de Neurociencias, Universidad Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Toni
authors.initials: T
authors.lastname: Cañete
authors.affiliation: Departamento de Psiquiatria y Medicina Legal, Instituto de Neurociencias, Universidad Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Blazquez
authors.affiliation: Departamento de Psiquiatria y Medicina Legal, Instituto de Neurociencias, Universidad Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Adolf
authors.initials: A
authors.lastname: Tobeña
authors.affiliation: Departamento de Psiquiatria y Medicina Legal, Instituto de Neurociencias, Universidad Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Fernandez-Teruel
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez-Maeso
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg and Frederiksberg Hospitals, Building 11B, 2nd floor, Bispebjerg Bakke 23, 2400, Copenhagen NV, Denmark. Susana.aznar.kleijn@regionh.dk.
authors.forename: Susana
authors.identifier: http://orcid.org/0000-0001-7940-6246
authors.initials: S
authors.lastname: Aznar
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D015870:Gene Expression; D008297:Male; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051381:Rats; D055647:Rats, Transgenic; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis* / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis* / Q000235:genetics; D013045:Species Specificity
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2
keywords: 5-HT2A; Epigenetics; GSK3β; Prefrontal cortex; Roman low- and high-avoidance rats; Schizophrenia; Striatum; mGluR2; β-Catenin