Article: article from journal or magazin.
Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
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.
Agmatine/metabolism, Agmatine/pharmacology, Animals, Behavior, Animal/drug effects, 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, Mice, Mice, Knockout, Microarray Analysis, Phenotype, Phosphorylation/drug effects, Polymerase Chain Reaction, Prefrontal Cortex/metabolism, Transcription Factors/genetics, Ureohydrolases/genetics
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