title: Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.
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.
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland.|Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: E M
authors.initials: EM
authors.lastname: Meylan
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland.|Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Breuillaud
authors.affiliation: Laboratory of Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Seredenina
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland.|Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.|Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: P J
authors.initials: PJ
authors.lastname: Magistretti
authors.affiliation: Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Halfon
authors.affiliation: Laboratory of Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.
authors.forename: R
authors.initials: R
authors.lastname: Luthi-Carter
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, University Medical Center, University of Lausanne, Prilly, Switzerland.|Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: J-R
authors.initials: JR
authors.lastname: Cardinaux
mesh_terms: D000376:Agmatine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003866:Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D017397:Prefrontal Cortex / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014512:Ureohydrolases / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C519509:Crtc1 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D018691:Excitatory Amino Acid Antagonists; D014157:Transcription Factors; D007649:Ketamine; D000376:Agmatine; D014512:Ureohydrolases; C019625:agmatinase