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.