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

Luna Fomsgaard; Jose L Moreno; Mario de la Fuente Revenga; Tomasz Brudek; Dea Adamsen; Cristobal Rio-Alamos; Justin Saunders; Anders Bue Klein; Ignasi Oliveras; Toni Cañete; Gloria Blazquez; Adolf Tobeña; Albert Fernandez-Teruel; Javier Gonzalez-Maeso; Susana Aznar

doi:10.1007/s12035-017-0457-y

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

Luna Fomsgaard, Jose L Moreno, Mario de la Fuente Revenga, Tomasz Brudek, Dea Adamsen, Cristobal Rio-Alamos, Justin Saunders, Anders Bue Klein, Ignasi Oliveras, Toni Cañete, Gloria Blazquez, Adolf Tobeña, Albert Fernandez-Teruel, Javier Gonzalez-Maeso, Susana Aznar

14 Citationer (Scopus)

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-HT2A and 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-HT2A binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT2A gene 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-HT1A receptor. 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-HT2A receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.

Originalsprog	Engelsk
Tidsskrift	Molecular Neurobiology
Vol/bind	55
Udgave nummer	3
Sider (fra-til)	1998–2012
ISSN	0893-7648
DOI	https://doi.org/10.1007/s12035-017-0457-y
Status	Udgivet - 1 mar. 2018

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10.1007/s12035-017-0457-y

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587367/Licens: Andet

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Fomsgaard, L., Moreno, J. L., de la Fuente Revenga, M., Brudek, T., Adamsen, D., Rio-Alamos, C., Saunders, J., Klein, A. B., Oliveras, I., Cañete, T., Blazquez, G., Tobeña, A., Fernandez-Teruel, A., Gonzalez-Maeso, J., & Aznar, S. (2018). 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. Molecular Neurobiology, 55(3), 1998–2012 . https://doi.org/10.1007/s12035-017-0457-y

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. / Fomsgaard, Luna; Moreno, Jose L; de la Fuente Revenga, Mario et al.
I: Molecular Neurobiology, Bind 55, Nr. 3, 01.03.2018, s. 1998–2012 .

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Fomsgaard, L, Moreno, JL, de la Fuente Revenga, M, Brudek, T, Adamsen, D, Rio-Alamos, C, Saunders, J, Klein, AB, Oliveras, I, Cañete, T, Blazquez, G, Tobeña, A, Fernandez-Teruel, A, Gonzalez-Maeso, J & Aznar, S 2018, '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', Molecular Neurobiology, bind 55, nr. 3, s. 1998–2012 . https://doi.org/10.1007/s12035-017-0457-y

Fomsgaard L, Moreno JL, de la Fuente Revenga M, Brudek T, Adamsen D, Rio-Alamos C et al. 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. Molecular Neurobiology. 2018 mar. 1;55(3):1998–2012 . doi: 10.1007/s12035-017-0457-y

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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-HT2A and 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-HT2A binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT2A gene 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-HT1A receptor. 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-HT2A receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.",

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AU - Fomsgaard, Luna

AU - Moreno, Jose L

AU - de la Fuente Revenga, Mario

AU - Brudek, Tomasz

AU - Adamsen, Dea

AU - Rio-Alamos, Cristobal

AU - Saunders, Justin

AU - Klein, Anders Bue

AU - Oliveras, Ignasi

AU - Cañete, Toni

AU - Blazquez, Gloria

AU - Tobeña, Adolf

AU - Fernandez-Teruel, Albert

AU - Gonzalez-Maeso, Javier

AU - Aznar, Susana

PY - 2018/3/1

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N2 - 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-HT2A and 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-HT2A binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT2A gene 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-HT1A receptor. 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-HT2A receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.

AB - 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-HT2A and 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-HT2A binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT2A gene 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-HT1A receptor. 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-HT2A receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.

KW - Journal Article

U2 - 10.1007/s12035-017-0457-y

DO - 10.1007/s12035-017-0457-y

M3 - Journal article

C2 - 28265857

SN - 0893-7648

VL - 55

SP - 1998

EP - 2012

JO - Molecular Neurobiology

JF - Molecular Neurobiology

IS - 3

ER -

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

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