Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression

Handle URI:
http://hdl.handle.net/10754/617287
Title:
Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression
Authors:
Meylan, E M; Breuillaud, L; Seredenina, T; Magistretti, Pierre J. ( 0000-0002-6678-320X ) ; Halfon, O; Luthi-Carter, R; Cardinaux, J-R
Abstract:
Recent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1−/− mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1−/− mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1−/− prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1−/− mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1−/− mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression 2016, 6 (7):e852 Translational Psychiatry
Publisher:
Springer Nature
Journal:
Translational Psychiatry
Issue Date:
12-Jul-2016
DOI:
10.1038/tp.2016.116
Type:
Article
ISSN:
2158-3188
Sponsors:
We thank Suzanne Badoux for her initial work with an agmatinase antibody that was not used in this study. This work was funded by a grant from the Swiss National Science Foundation (31003A-135692) and partly supported by the National Centre of Competence in Research (NCCR) Synapsy.
Additional Links:
http://www.nature.com/doifinder/10.1038/tp.2016.116
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DC FieldValue Language
dc.contributor.authorMeylan, E Men
dc.contributor.authorBreuillaud, Len
dc.contributor.authorSeredenina, Ten
dc.contributor.authorMagistretti, Pierre J.en
dc.contributor.authorHalfon, Oen
dc.contributor.authorLuthi-Carter, Ren
dc.contributor.authorCardinaux, J-Ren
dc.date.accessioned2016-07-21T10:10:19Z-
dc.date.available2016-07-21T10:10:19Z-
dc.date.issued2016-07-12-
dc.identifier.citationInvolvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression 2016, 6 (7):e852 Translational Psychiatryen
dc.identifier.issn2158-3188-
dc.identifier.doi10.1038/tp.2016.116-
dc.identifier.urihttp://hdl.handle.net/10754/617287-
dc.description.abstractRecent studies implicate the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brains of mood disorder patients. We have previously shown that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate behavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. Here, the molecular basis of the behavioral phenotype of Crtc1−/− mice was further examined using microarray gene expression profiling that revealed an upregulation of Agmat in the cortex of Crtc1−/− mice. Quantitative polymerase chain reaction and western blot analyses confirmed Agmat upregulation in the Crtc1−/− prefrontal cortex (PFC) and hippocampus, which were further demonstrated by confocal immunofluorescence microscopy to comprise an increased number of Agmat-expressing cells, notably parvalbumin- and somatostatin-positive interneurons. Acute agmatine and ketamine treatments comparably improved the depressive-like behavior of male and female Crtc1−/− mice in the forced swim test, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit because of upregulated Agmat. Agmatine rapidly increased brain-derived neurotrophic factor (BDNF) levels only in the PFC of wild-type (WT) females, and decreased eukaryotic elongation factor 2 (eEF2) phosphorylation in the PFC of male and female WT mice, indicating that agmatine might be a fast-acting antidepressant with N-methyl-D-aspartate (NMDA) receptor antagonist properties. Collectively, these findings implicate Agmat in the depressive-like phenotype of Crtc1−/− mice, refine current understanding of the agmatinergic system in the brain and highlight its putative role in major depression.en
dc.description.sponsorshipWe thank Suzanne Badoux for her initial work with an agmatinase antibody that was not used in this study. This work was funded by a grant from the Swiss National Science Foundation (31003A-135692) and partly supported by the National Centre of Competence in Research (NCCR) Synapsy.en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.relation.urlhttp://www.nature.com/doifinder/10.1038/tp.2016.116en
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en
dc.titleInvolvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depressionen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalTranslational Psychiatryen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionCenter for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerlanden
dc.contributor.institutionService of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerlanden
dc.contributor.institutionLaboratory of Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerlanden
dc.contributor.institutionLaboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerlanden
dc.contributor.institutionDepartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UKen
dc.contributor.institutionDepartment of Pharmacology and Therapeutics, McGill University, Montréal, Canada.en
dc.contributor.institutionDepartment of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland.en
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorMagistretti, Pierre J.en
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