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Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression.

ABSTRACT: Fluoxetine, one of the selective serotonin reuptake inhibitor (SSRI) antidepressants, has been thought to be effective for treating post-stroke depression (PSD). Recent work has shown that fluoxetine may exert an antidepressive effect through increasing the level of brain-derived neurotrophic factor (BDNF), but the underlying mechanism still remains unclear. In the present study, we successfully established the PSD model using male C57BL/6?J mice by photothrombosis of the left anterior cortex combined with isolatied-housing conditions. In the process, we confirmed that fluoxetine could improve the depression-like behaviors of PSD mice and upregulate the expression of BDNF in the hippocampus. However, depletion of BDNF by transfecting lentivirus-derived shBDNF in hippocampus suppressed the effect of fluoxetine. Furthermore, we demonstrated the epigenetic mechanisms involved in regulation of BDNF expression induced by fluoxetine. We found a statistically significant increase in DNA methylation at specific CpG sites (loci 2) of Bdnf promoter IV in the hippocampus of PSD mice. We also found that fluoxetine treatment could disassociate the MeCP2-CREB-Bdnf promoter IV complex via phosphorylation of MeCP2 at Ser421 by Protein Kinase A (PKA). Our research highlighted the importance of fluoxetine in regulating BDNF expression which could represent a potential strategy for preventing PSD.

SUBMITTER: Jin HJ

PROVIDER: S-EPMC5668242 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression.

Jin Hui-Juan HJ Pei Lei L Li Ya-Nan YN Zheng Hui H Yang Shuai S Wan Yan Y Mao Ling L Xia Yuan-Peng YP He Quan-Wei QW Li Man M Yue Zhen-Yu ZY Hu Bo B

Scientific reports 20171102 1

Fluoxetine, one of the selective serotonin reuptake inhibitor (SSRI) antidepressants, has been thought to be effective for treating post-stroke depression (PSD). Recent work has shown that fluoxetine may exert an antidepressive effect through increasing the level of brain-derived neurotrophic factor (BDNF), but the underlying mechanism still remains unclear. In the present study, we successfully established the PSD model using male C57BL/6 J mice by photothrombosis of the left anterior cortex co ...[more]

PMID: 29097744

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Project description:ObjectiveAdolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors.MethodKnock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed.ResultsWe identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNFMet/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence.ConclusionsThese findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

Project description:AimsMorinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive-like behaviors in post-stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation.MethodsBehavioral tests were performed to evaluate the effect of MOOs on depressive-like behaviors in PSD rats. The effects of MOOs on the expression of IL-18, IL-1β, and nucleotide-binding domain leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence and Western blot analysis. Adeno-associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence.ResultsMOOs can alleviate depressive-like behaviors in PSD rats. PSD rats showed increased expression of IL-18, IL-1β, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive-like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive-like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL-18, IL-1β, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF-κB p65 signaling pathway.ConclusionOverall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.

Dataset Information

Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression.

Publications

Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression.

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