2381/41750 E. M. Meylan E. M. Meylan L. Breuillaud L. Breuillaud T. Seredenina T. Seredenina P. J. Magistretti P. J. Magistretti O. Halfon O. Halfon Ruth Luthi-Carter Ruth Luthi-Carter J-R. Cardinaux J-R. Cardinaux Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression. University of Leicester 2018 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 2018-04-25 14:45:15 Journal contribution https://figshare.le.ac.uk/articles/journal_contribution/Involvement_of_the_agmatinergic_system_in_the_depressive-like_phenotype_of_the_Crtc1_knockout_mouse_model_of_depression_/10234217 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.