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M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS

BACKGROUND: Early-life stress is a key risk for psychiatric disorders that may produce changes in the neurodevelopment. N-methyl-d-aspartate receptor (NMDAR) have been associated with the pathophysiology of schizophrenia and evidence supports that epigenetic changes in NMDAR imply deficiencies in ex...

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Autores principales: Loureiro, Camila, Helene Aparecida, Fachim, Fabiana, Corsi-Zuelli, Rosana, Shuhama, Lourenço, Joca Sâmia Regiane, Paulo Rossi, Menezes, Caroline, F Dalton, Cristina Marta, Del-Ben, Paulo, Louzada-Junior, Reynolds, Gavin P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233950/
http://dx.doi.org/10.1093/schbul/sbaa030.321
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author Loureiro, Camila
Helene Aparecida, Fachim
Fabiana, Corsi-Zuelli
Rosana, Shuhama
Lourenço, Joca Sâmia Regiane
Paulo Rossi, Menezes
Caroline, F Dalton
Cristina Marta, Del-Ben
Paulo, Louzada-Junior
Reynolds, Gavin P
author_facet Loureiro, Camila
Helene Aparecida, Fachim
Fabiana, Corsi-Zuelli
Rosana, Shuhama
Lourenço, Joca Sâmia Regiane
Paulo Rossi, Menezes
Caroline, F Dalton
Cristina Marta, Del-Ben
Paulo, Louzada-Junior
Reynolds, Gavin P
author_sort Loureiro, Camila
collection PubMed
description BACKGROUND: Early-life stress is a key risk for psychiatric disorders that may produce changes in the neurodevelopment. N-methyl-d-aspartate receptor (NMDAR) have been associated with the pathophysiology of schizophrenia and evidence supports that epigenetic changes in NMDAR imply deficiencies in excitatory neurotransmission suggest its role in the neurobiology of psychoses (Uno and Coyle, 2019; Fachim et al., 2019; Gulchina et al., 2017). Aims: Although previous studies have shown abnormalities in the glutamatergic system in animal model of schizophrenia, it is not known if there are equivalent mRNA/protein alterations and DNA methylation changes in the brains of rats reared in isolation. Thus, in order to improve the knowledge of glutamatergic system role in psychosis, we investigated the NR1 and NR2 mRNA/protein and the DNA methylation levels of Grin1, Grin2a and Grin2b promoter region in the prefrontal cortex (PFC) and hippocampus (HIPPO) of male Wistar rats after isolation rearing. Furthermore, because the Parvalbumin (PV) deficit is the most consistent finding across animal models and schizophrenia itself, we also evaluated the expression of PV and other related GABAergic genes (REL and GAD1) in the brain of rats undergoing social isolation rearing as a validation of this animal model. We hypothesized that isolation rearing reduces mRNA and protein expressions of NMDAR subunits and cause DNA methylation changes. METHODS: Wistar rats were kept isolated or grouped (n=10/group) from weaning (21 days after birth) to 10 weeks and then exposed to the Open Field Test to assess locomotion. Afterwards the behavioural tests, the tissues were dissected for RNA/DNA extraction and NMDAR subunits were analysed using qRT-PCR, ELISA and pyrosequencing. Data were analysed by parametric tests. RESULTS: Isolated-reared animals presented: (i) decreased mRNA levels of Grin1 (p=0.011), Grin2a (p=0.039) and Grin2b (p=0.037) in the PFC followed by reduction in the GABAergic markers; (ii) increased NR1 protein levels in the HIPPO (p=0.001); (iii) hypermethylation of Grin1 at CpG5 in the PFC (p=0.047) and Grin2b CpG4 in the HIPPO when compared to grouped (p=0.024). Moreover, isolated and grouped animals presented a negative correlation between Grin1 mRNA and Grin1 methylation levels at CpG5 in the PFC (r: -0.577; p=0.010) and isolated rats presented a negative correlation between Grin2b methylation at CpG4 and NR2 protein levels in the HIPPO (r: -0.753; p=0.012). DISCUSSION: This study supports the hypothesis that the NMDAR methylation changes found in the brain tissues may underlie the NMDAR mRNA/protein expression alterations caused by the isolation period. These results highlighted the importance of the environmental influence during the development that may lead to cognitive impairments in adulthood. Moreover, we demonstrated that the social isolation rearing during 10 weeks causes long-lasting behavioral changes that may be more associated with late stages of schizophrenia. Our study contributes to the identification of the epigenetic mechanisms involved in the neuropathophysiology of schizophrenia, which can bring new pharmacotherapeutic strategies and to identify biomarkers that can improve the early interventions in schizophrenia patients. Finally, our data thus reinforce the validity of rats reared in social isolation after weaning in modelling aspects of schizophrenia, highlighting the glutamatergic and GABAergic features involved principally in the cognitive impairments related to prefrontal cortex.
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spelling pubmed-72339502020-05-23 M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS Loureiro, Camila Helene Aparecida, Fachim Fabiana, Corsi-Zuelli Rosana, Shuhama Lourenço, Joca Sâmia Regiane Paulo Rossi, Menezes Caroline, F Dalton Cristina Marta, Del-Ben Paulo, Louzada-Junior Reynolds, Gavin P Schizophr Bull Poster Session II BACKGROUND: Early-life stress is a key risk for psychiatric disorders that may produce changes in the neurodevelopment. N-methyl-d-aspartate receptor (NMDAR) have been associated with the pathophysiology of schizophrenia and evidence supports that epigenetic changes in NMDAR imply deficiencies in excitatory neurotransmission suggest its role in the neurobiology of psychoses (Uno and Coyle, 2019; Fachim et al., 2019; Gulchina et al., 2017). Aims: Although previous studies have shown abnormalities in the glutamatergic system in animal model of schizophrenia, it is not known if there are equivalent mRNA/protein alterations and DNA methylation changes in the brains of rats reared in isolation. Thus, in order to improve the knowledge of glutamatergic system role in psychosis, we investigated the NR1 and NR2 mRNA/protein and the DNA methylation levels of Grin1, Grin2a and Grin2b promoter region in the prefrontal cortex (PFC) and hippocampus (HIPPO) of male Wistar rats after isolation rearing. Furthermore, because the Parvalbumin (PV) deficit is the most consistent finding across animal models and schizophrenia itself, we also evaluated the expression of PV and other related GABAergic genes (REL and GAD1) in the brain of rats undergoing social isolation rearing as a validation of this animal model. We hypothesized that isolation rearing reduces mRNA and protein expressions of NMDAR subunits and cause DNA methylation changes. METHODS: Wistar rats were kept isolated or grouped (n=10/group) from weaning (21 days after birth) to 10 weeks and then exposed to the Open Field Test to assess locomotion. Afterwards the behavioural tests, the tissues were dissected for RNA/DNA extraction and NMDAR subunits were analysed using qRT-PCR, ELISA and pyrosequencing. Data were analysed by parametric tests. RESULTS: Isolated-reared animals presented: (i) decreased mRNA levels of Grin1 (p=0.011), Grin2a (p=0.039) and Grin2b (p=0.037) in the PFC followed by reduction in the GABAergic markers; (ii) increased NR1 protein levels in the HIPPO (p=0.001); (iii) hypermethylation of Grin1 at CpG5 in the PFC (p=0.047) and Grin2b CpG4 in the HIPPO when compared to grouped (p=0.024). Moreover, isolated and grouped animals presented a negative correlation between Grin1 mRNA and Grin1 methylation levels at CpG5 in the PFC (r: -0.577; p=0.010) and isolated rats presented a negative correlation between Grin2b methylation at CpG4 and NR2 protein levels in the HIPPO (r: -0.753; p=0.012). DISCUSSION: This study supports the hypothesis that the NMDAR methylation changes found in the brain tissues may underlie the NMDAR mRNA/protein expression alterations caused by the isolation period. These results highlighted the importance of the environmental influence during the development that may lead to cognitive impairments in adulthood. Moreover, we demonstrated that the social isolation rearing during 10 weeks causes long-lasting behavioral changes that may be more associated with late stages of schizophrenia. Our study contributes to the identification of the epigenetic mechanisms involved in the neuropathophysiology of schizophrenia, which can bring new pharmacotherapeutic strategies and to identify biomarkers that can improve the early interventions in schizophrenia patients. Finally, our data thus reinforce the validity of rats reared in social isolation after weaning in modelling aspects of schizophrenia, highlighting the glutamatergic and GABAergic features involved principally in the cognitive impairments related to prefrontal cortex. Oxford University Press 2020-05 2020-05-18 /pmc/articles/PMC7233950/ http://dx.doi.org/10.1093/schbul/sbaa030.321 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Poster Session II
Loureiro, Camila
Helene Aparecida, Fachim
Fabiana, Corsi-Zuelli
Rosana, Shuhama
Lourenço, Joca Sâmia Regiane
Paulo Rossi, Menezes
Caroline, F Dalton
Cristina Marta, Del-Ben
Paulo, Louzada-Junior
Reynolds, Gavin P
M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS
title M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS
title_full M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS
title_fullStr M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS
title_full_unstemmed M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS
title_short M9. RATS REARED IN SOCIAL ISOLATION INDUCES EPIGENETIC MODIFICATIONS IN THE NMDA RECEPTOR SUBUNITS
title_sort m9. rats reared in social isolation induces epigenetic modifications in the nmda receptor subunits
topic Poster Session II
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233950/
http://dx.doi.org/10.1093/schbul/sbaa030.321
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