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

• Published in: Translational psychiatry 2016-07, Vol.6 (7), p.e852-e852
• Main Authors: Meylan, E M, Breuillaud, L, Seredenina, T, Magistretti, P J, Halfon, O, Luthi-Carter, R, Cardinaux, J-R
• Format: Article
• Language: English
• Subjects: 14/19; 38/1; 38/61; 631/378/340; 64/110; 692/699/476/1414; 82/29; 82/80; Agmatine - metabolism; Agmatine - pharmacology; Animals; Behavior, Animal - drug effects; Behavioral Sciences; Biological Psychology; Blotting, Western; Brain - metabolism; Brain-Derived Neurotrophic Factor - drug effects; Brain-Derived Neurotrophic Factor - metabolism; Cerebral Cortex - metabolism; Depressive Disorder - genetics; Depressive Disorder - metabolism; Depressive Disorder - psychology; Eukaryotic Initiation Factor-2 - drug effects; Eukaryotic Initiation Factor-2 - metabolism; Excitatory Amino Acid Antagonists - pharmacology; Female; Gene Expression Profiling; Hippocampus - metabolism; Interneurons - metabolism; Ketamine - pharmacology; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Microarray Analysis; Neurosciences; Original; original-article; Pharmacotherapy; Phenotype; Phosphorylation - drug effects; Polymerase Chain Reaction; Prefrontal Cortex - metabolism; Psychiatry; Transcription Factors - genetics; Ureohydrolases - genetics
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2016.116

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.