Meylan EM Breuillaud L Seredenina T Magistretti PJ Halfon O Luthi-Carter R Cardinaux JR 2016 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. https://sonar.ch/global/documents/246440 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/tp.2016.116 info:eu-repo/semantics/altIdentifier/pmid/27404284 Translational psychiatry. - 2016 Agmatine Animals Behavior, Animal Blotting, Western Brain Brain-Derived Neurotrophic Factor Cerebral Cortex Depressive Disorder Eukaryotic Initiation Factor-2 Excitatory Amino Acid Antagonists Female Gene Expression Profiling Hippocampus Interneurons Ketamine Male Mice Mice, Knockout Microarray Analysis Phenotype Phosphorylation Polymerase Chain Reaction Prefrontal Cortex Transcription Factors Ureohydrolases Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression. http://purl.org/coar/resource_type/c_6501