title: Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide.
abstract: Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1-3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 17 177 Stockholm, Sweden; tomas.hokfelt@ki.se Swapnali.Barde@ki.se.
authors.forename: Swapnali
authors.initials: S
authors.lastname: Barde
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, 17 177 Stockholm, Sweden.|The Center for Molecular Medicine, 17 177 Stockholm, Sweden.|Swedish Toxicology Science Research Center Swetox, 151 36 Södertälje, Sweden.
authors.forename: Joelle
authors.initials: J
authors.lastname: Rüegg
authors.affiliation: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC H4H 1R3, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Prud'homme
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, 17 177 Stockholm, Sweden.|The Center for Molecular Medicine, 17 177 Stockholm, Sweden.
authors.forename: Tomas J
authors.initials: TJ
authors.lastname: Ekström
authors.affiliation: Neuromorphological and Neuroendocrine Research Laboratory, Hungarian Academy of Sciences, Semmelweis University, H-1085, Budapest, Hungary.|Department of Anatomy, Histology and Embryology, Semmelweis University, H-1085, Budapest, Hungary.|Human Brain Tissue Bank and Laboratory, Semmelweis University, H-1085, Budapest, Hungary.
authors.forename: Miklos
authors.initials: M
authors.lastname: Palkovits
authors.affiliation: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC H4H 1R3, Canada.|Department of Psychiatry, McGill University, Montreal, QC, H3A 0G4, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, H-1089, Budapest, Hungary.|Magyar Tudományos Akadémia-Semmelweis Egyetem (MTA-SE)-Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, H-1089, Budapest, Hungary.|Nemzeti Agykutatási Program-A alprogram-Semmelweis Egyetem (NAP-A-SE) Research Group, Semmelweis University, H-1089, Budapest, Hungary.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bagdy
authors.affiliation: Department of Clinical Chemistry, Linköping University, 581 83 Linköping, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Ihnatko
authors.affiliation: Department of Clinical Chemistry, Linköping University, 581 83 Linköping, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
authors.forename: Elvar
authors.initials: E
authors.lastname: Theodorsson
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, H-1089, Budapest, Hungary.|Magyar Tudományos Akadémia, Semmelweis Egyetem, Nemzeti Agykutatási Program B alprogram (MTA-SE-NAP B) Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Semmelweis University, H-1089, Budapest, Hungary.|Neuroscience and Psychiatry Unit, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhasz
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 17 177 Stockholm, Sweden.
authors.forename: Rochellys
authors.initials: R
authors.lastname: Diaz-Heijtz
authors.affiliation: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC H4H 1R3, Canada.|Department of Psychiatry, McGill University, Montreal, QC, H3A 0G4, Canada.
authors.forename: Naguib
authors.initials: N
authors.lastname: Mechawar
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 17 177 Stockholm, Sweden; tomas.hokfelt@ki.se Swapnali.Barde@ki.se.
authors.forename: Tomas G M
authors.initials: TG
authors.lastname: Hökfelt
mesh_terms: D000328:Adult; D000339:Affect; D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001931:Brain Mapping; D016022:Case-Control Studies; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism*; D065847:Dorsal Raphe Nucleus / Q000378:metabolism; D005260:Female; D019004:Galanin / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D044091:Receptor, Galanin, Type 1 / Q000235:genetics / Q000378:metabolism*; D044093:Receptor, Galanin, Type 3 / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D013405:Suicide
chemical_list: C056567:GAL protein, human; D044091:Receptor, Galanin, Type 1; D044093:Receptor, Galanin, Type 3; D019004:Galanin
keywords: epigenetics; human postmortem brain; neuropeptides; stress; transmitter coexistence