Cargando…

Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression

BACKGROUND: Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and...

Descripción completa

Detalles Bibliográficos
Autores principales: Sequeira, Adolfo, Mamdani, Firoza, Ernst, Carl, Vawter, Marquis P., Bunney, William E., Lebel, Veronique, Rehal, Sonia, Klempan, Tim, Gratton, Alain, Benkelfat, Chawki, Rouleau, Guy A., Mechawar, Naguib, Turecki, Gustavo
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719799/
https://www.ncbi.nlm.nih.gov/pubmed/19668376
http://dx.doi.org/10.1371/journal.pone.0006585
_version_ 1782170103805116416
author Sequeira, Adolfo
Mamdani, Firoza
Ernst, Carl
Vawter, Marquis P.
Bunney, William E.
Lebel, Veronique
Rehal, Sonia
Klempan, Tim
Gratton, Alain
Benkelfat, Chawki
Rouleau, Guy A.
Mechawar, Naguib
Turecki, Gustavo
author_facet Sequeira, Adolfo
Mamdani, Firoza
Ernst, Carl
Vawter, Marquis P.
Bunney, William E.
Lebel, Veronique
Rehal, Sonia
Klempan, Tim
Gratton, Alain
Benkelfat, Chawki
Rouleau, Guy A.
Mechawar, Naguib
Turecki, Gustavo
author_sort Sequeira, Adolfo
collection PubMed
description BACKGROUND: Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations. METHODOLOGY/PRINCIPAL FINDINGS: We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data. CONCLUSIONS/SIGNIFICANCE: The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.
format Text
id pubmed-2719799
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-27197992009-08-11 Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression Sequeira, Adolfo Mamdani, Firoza Ernst, Carl Vawter, Marquis P. Bunney, William E. Lebel, Veronique Rehal, Sonia Klempan, Tim Gratton, Alain Benkelfat, Chawki Rouleau, Guy A. Mechawar, Naguib Turecki, Gustavo PLoS One Research Article BACKGROUND: Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations. METHODOLOGY/PRINCIPAL FINDINGS: We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data. CONCLUSIONS/SIGNIFICANCE: The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions. Public Library of Science 2009-08-11 /pmc/articles/PMC2719799/ /pubmed/19668376 http://dx.doi.org/10.1371/journal.pone.0006585 Text en Sequeira et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sequeira, Adolfo
Mamdani, Firoza
Ernst, Carl
Vawter, Marquis P.
Bunney, William E.
Lebel, Veronique
Rehal, Sonia
Klempan, Tim
Gratton, Alain
Benkelfat, Chawki
Rouleau, Guy A.
Mechawar, Naguib
Turecki, Gustavo
Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression
title Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression
title_full Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression
title_fullStr Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression
title_full_unstemmed Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression
title_short Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression
title_sort global brain gene expression analysis links glutamatergic and gabaergic alterations to suicide and major depression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719799/
https://www.ncbi.nlm.nih.gov/pubmed/19668376
http://dx.doi.org/10.1371/journal.pone.0006585
work_keys_str_mv AT sequeiraadolfo globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT mamdanifiroza globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT ernstcarl globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT vawtermarquisp globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT bunneywilliame globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT lebelveronique globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT rehalsonia globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT klempantim globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT grattonalain globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT benkelfatchawki globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT rouleauguya globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT mechawarnaguib globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression
AT tureckigustavo globalbraingeneexpressionanalysislinksglutamatergicandgabaergicalterationstosuicideandmajordepression