Dataset Information

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway.

ABSTRACT:

Background

Phosphodiesterase 4D (PDE4D) inhibitor is commonly used to treat depression, but side effects seriously decrease its efficacy. PDE4D was a downstream target mRNA of miR-139-5p. Therefore, we examined the effects of hippocampal miR-139-5p gain- and loss-of-function on depression-like behaviors, the expression level of PDE4D, and hippocampus neurogenesis.

Methods

Bioinformatic analyses were carried out to to screen differential genes. Quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay were used to confirm the relationship between miR-139-5p and PDE4D. MiR-139-5p mimics, miR-139-5p inhibitor, or miR-NC were used to explore the function of miR-139-5p in HT-22 cells. We further explored the role of miR-139-5p in vivo using AAV-injection. Elisa, western blotting, and fluorescence in situ hybridization (FISH) were used to detect the expression of miR-139-5p and PDE4D in CRC tissues.

Results

Here, we showed that PDE4D messenger RNA (mRNA) was a direct target of microRNA (miR)-139-5p, which was downregulated in a chronic ultra-mild stress (CUMS)-induced depression mouse model. Moreover, in experiments in vitro, miR-139-5p mimic repressed PDE4D expression in HT-22 cells, but promoted phosphorylated cyclic-AMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. Interestingly, adeno-associated virus (AAV)-miR-139-5p downregulated susceptibility to stress-induced depression-like behaviors in mice. AAV-miR-139-5p suppressed PDE4D in mouse hippocampal cells, increasing expression level of cyclic adenosine monophosphate (cAMP), p-CREB, and BDNF, and stimulating mouse hippocampal neurogenesis.

Conclusions

Our findings suggested that miR-139-5p acted like an antidepressant by targeting PDE4D, thereby regulating the cAMP/protein kinase A (PKA)/CREB/BDNF pathway to improve depression.

SUBMITTER: Huang P

PROVIDER: S-EPMC8576692 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway.

Huang Peng P Wei Songren S Luo Meng M Tang Zhuohong Z Lin Qingmei Q Wang Xing X Luo Mi M He Yanjun Y Wang Chuan C Wei Dezhan D Xia Chenglai C Xu Jiangping J

Annals of translational medicine 20211001 20

<h4>Background</h4>Phosphodiesterase 4D (PDE4D) inhibitor is commonly used to treat depression, but side effects seriously decrease its efficacy. PDE4D was a downstream target mRNA of miR-139-5p. Therefore, we examined the effects of hippocampal miR-139-5p gain- and loss-of-function on depression-like behaviors, the expression level of PDE4D, and hippocampus neurogenesis.<h4>Methods</h4>Bioinformatic analyses were carried out to to screen differential genes. Quantitative real-time polymerase cha ...[more]

PMID: 34790800

Similar Datasets

Project description:BackgroundSemen Cuscutae flavonoids (SCFs) constitute a class of metabolites of Semen Cuscutae, a botanical drug that was recently found to have an anti-depression effect. This study aimed to evaluate the anti-depression effects of SCFs in chronic unpredictable mild stress (CUMS)-induced mice and to interrogate the underlying mechanisms.Materials and methodsThe CUMS mice were used for assessing the effects of SCFs treatments on depression. Mice were randomly divided into five groups. Four groups were subjected to the CUMS induction and concomitantly administered orally with either the vehicle or with a high-, medium-, and low-dose of SCFs, once per day for 4 weeks. One group was kept untreated as a control. The mice were then assessed for their statuses of a number of depression-related parameters, including body weight, food intake, sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swim test (FST). In addition, a day after the completion of these tests, biopsies from the hippocampus were harvested and used to perform metabolomics by HPLC-MS/MS and to assess the levels of cAMP by ELISA and the levels of PKA, CREB, p-CREB, and BDNF by Western blot analyses.ResultsSCFs resulted in significant increases in both body weight and food intake and in the amelioration of the depressive-like behaviors in CUMS mice. A high-dose SCFs treatment led to significant alterations in 72 metabolites, of which 26 were identified as potential biomarkers for the SCFs treatment. These metabolites are associated with lipid, amino acid, and nucleotide metabolism. Among 26 metabolites, cAMP was positively correlated with body weight, SPT, OFT-total distance, and OFT-central residence time, while negatively correlated with immobility time in TST and FST, linking a change in cAMP with the SCFs treatment and the significant improvement in depressive symptoms in CUMS mice. Further analyses revealed that the levels of cAMP, PKA, CREB, p-CREB, and BDNF were reduced in the hippocampus of CUMS mice but were all increased following the SCFs treatments.ConclusionSCFs could ameliorate hippocampal metabolic disturbances and depressive behaviors and cause the activation of the cAMP-PKA-CREB-BDNF signaling pathway in the hippocampus of CUMS mice.

Dataset Information

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway.

Background

Methods

Results

Conclusions

Publications

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway.

Similar Datasets

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