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

ABSTRACT: 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.

SUBMITTER: Meylan EM

PROVIDER: S-EPMC5545706 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Meylan E M EM Breuillaud L L Seredenina T T Magistretti P J PJ Halfon O O Luthi-Carter R R Cardinaux J-R JR

Translational psychiatry 20160712 7

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, t ...[more]

PMID: 27404284

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Project description:Purpose:Recessive mutations in the human IQCB1/NPHP5 gene are associated with Senior-Løken syndrome (SLS), a ciliopathy presenting with nephronophthisis and Leber congenital amaurosis (LCA). Nphp5-knockout mice develop LCA without nephronophthisis. Mutant rods rapidly degenerate while mutant cones survive for months. The purpose of this study was to reinitiate cone ciliogenesis in a Nphp5 -/-; Nrl -/- mouse with viral expression of full-length NPHP5 and rescue function. Methods:Nphp5 -/- mice were mated with Nrl -/- mice to generate Nphp5-/-; Nrl-/- double-knockouts. Nphp5-/-; Nrl-/- mice and Nphp5+/-; Nrl-/- controls were phenotyped with confocal microscopy from postnatal day 10 (P10) until 6 months of age. Nphp5-/-; Nrl-/- mice and Nphp5+/-; Nrl-/- controls were injected at P15 with self-complementary adenoassociated virus 8 (Y733F) (AAV8(Y733F)) expressing GRK1-FL-cNPHP5. Expression of mutant NPHP5 was verified with confocal microscopy and electroretinography (ERG). Results:In the Nphp5 -/- and cone-only Nphp5 -/-; Nrl -/- mice, cone outer segments did not form, but mutant cones continued to express cone pigments in the inner segments without obvious signs of cone cell death. The mutant cone outer nuclear layer (ONL) and the inner segments were stable for more than 6 months in the cone-only Nphp5 -/-; Nrl -/- retinas. Viral expression of NPHP5 initiated after eye opening showed that connecting cilia and RP1-positive axonemes were formed. Furthermore, cone pigments and other cone outer segment proteins (cone transducin and cone PDE6) were present in the nascent mutant cone outer segments, and rescued mutant cones exhibited a significant photopic b-wave (30% of Nphp5 +/-; Nrl -/- controls). Conclusions:Nphp5-/-; Nrl-/- cones persistently express cone pigments in the inner segments without obvious degeneration, providing an extended duration interval for viral gene expression. Viral expression of full-length NPHP5 initiates ciliogenesis between P15 and P60, and mutant cones are, in part, functional, encouraging future retina gene replacement therapy.

Dataset Information

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

Publications

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

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