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Gene expression analysis in cortex of CRTC1 deficient mice and WT littermates

ABSTRACT: To identify gene expression changes associated with Crtc1 deficiency, we performed genome-wide transcriptome profile analyses by using mouse cDNA microarrays in the cortex of Crtc1‒/‒ and WT female mice BACKGROUND: Recent studies involve 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 brain of mood disorders patients. We showed that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate neurobehavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. METHODS: The molecular basis of the behavioral phenotype of Crtc1‒/‒ mice was further examined using microarray analysis. We characterized Agmat expression in the prefrontal cortex (PFC) and hippocampus (HIP) by quantitative polymerase chain reaction (qPCR), Western blot (WB) analysis, and confocal immunofluorescence microscopy. The antidepressant effect of agmatine was assessed by the forced swim test (FST). Brain-derived neurotrophic factor (BDNF) levels and eukaryotic elongation factor 2 (eEF2) phosphorylation were measured by WB. RESULTS: Microarray, qPCR and WB analyses revealed an upregulation of Agmat in Crtc1‒/‒ PFC and HIP, where immunofluorescence microscopy showed more Agmat-expressing cells, notably parvalbumin- and somatostatin-interneurons. Acute agmatine treatment efficiently improved depressive-like behavior of Crtc1‒/‒ mice in the FST, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit induced by upregulated Agmat. In WT mice, agmatine rapidly increased BDNF levels and eEF2 dephosphorylation, indicating that it might be a fast–acting antidepressant with NMDA receptor antagonist properties. CONCLUSIONS: Collectively, these findings support the involvement of the agmatinergic system in the depressive-like phenotype of Crtc1‒/‒ mice, and allow a better understanding of the agmatinergic system and its putative role in major depression.

ORGANISM(S): Mus musculus

PROVIDER: GSE80633 | GEO | 2016/07/18

SECONDARY ACCESSION(S): PRJNA319550

REPOSITORIES: GEO

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Project description:To identify gene expression changes associated with Crtc1 deficiency, we performed genome-wide transcriptome profile analyses by using mouse cDNA microarrays in the cortex of Crtc1â/â and WT female mice BACKGROUND: Recent studies involve 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 brain of mood disorders patients. We showed that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate neurobehavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. METHODS: The molecular basis of the behavioral phenotype of Crtc1â/â mice was further examined using microarray analysis. We characterized Agmat expression in the prefrontal cortex (PFC) and hippocampus (HIP) by quantitative polymerase chain reaction (qPCR), Western blot (WB) analysis, and confocal immunofluorescence microscopy. The antidepressant effect of agmatine was assessed by the forced swim test (FST). Brain-derived neurotrophic factor (BDNF) levels and eukaryotic elongation factor 2 (eEF2) phosphorylation were measured by WB. RESULTS: Microarray, qPCR and WB analyses revealed an upregulation of Agmat in Crtc1â/â PFC and HIP, where immunofluorescence microscopy showed more Agmat-expressing cells, notably parvalbumin- and somatostatin-interneurons. Acute agmatine treatment efficiently improved depressive-like behavior of Crtc1â/â mice in the FST, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit induced by upregulated Agmat. In WT mice, agmatine rapidly increased BDNF levels and eEF2 dephosphorylation, indicating that it might be a fastâacting antidepressant with NMDA receptor antagonist properties. CONCLUSIONS: Collectively, these findings support the involvement of the agmatinergic system in the depressive-like phenotype of Crtc1â/â mice, and allow a better understanding of the agmatinergic system and its putative role in major depression. RNA from cortex of 5 WT and 5 KO mice was used

Project description:Background: Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signaling during inflammation, is dysregulated in many chronic inflammatory disorders, however its role in depression and the associated sex differences have yet to be explored. Here we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. Methods: Male and female rats were treated with vehicle or DMF (25 mg/kg) while subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Hippocampal (HIP) microglial activation and alterations in gene transcripts were also evaluated. Results: DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, however DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Lastly, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, several differentially expressed genes in males were related to inflammatory or immune responses. Conclusions: Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression. Major depressive disorder is two times more prevalent in females than males. Further, immune system dysfunction has been shown to contribute to the development of depression, with previous studies consistently reporting chronic low-grade inflammation in depressed individuals. Not surprisingly, the immune system dysfunction associated with depression appears to be sex specific. As such, while anti-inflammatory drugs have shown antidepressant effects in preclinical studies, the sex differences in these effects are seldomly investigated. Thus, this study sought to determine the sex-specific antidepressant and immune modulatory effects of dimethyl fumarate (DMF) treatment. DMF is a drug that activates the protein nuclear factor erythroid 2-related factor 2 to initiate anti-inflammatory signaling pathways. Here, male and female rats were exposed to 8 weeks of chronic stress while receiving daily DMF treatment. Subsequently, their expression of depression- and anxiety-like behaviours, as well as learning and memory deficits were assessed. Changes in the levels of an inflammatory marker in the brain and alterations in gene expression were also evaluated. DMF treatment had antidepressant effects in male rats only but did not have anti-anxiety effects in either sex. The learning and memory deficits in both sexes were rescued with DMF treatment. Notably, chronic stress only increased inflammatory marker levels in male rats, which was prevented by DMF treatment. Additionally, DMF normalized several of the sex-specific gene alterations induced by chronic stress, with many of the male-specific genes relating to inflammatory processes. These data suggest that anti-inflammatory drugs may be an effective antidepressant treatment in males.

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Gene expression analysis in cortex of CRTC1 deficient mice and WT littermates

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