Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress

Cai, Zixuan; Ye, Ting; Xu, Xingshun; Gao, Minhui; Zhang, Yaru; Wang, Dan; Gu, Yiming; Zhu, Haojie; Tong, Lijuan; Lu, Jiashu; Chen, Zhuo; Huang, Chao

doi:10.1016/j.pnpbp.2020.109931

Cited by 32 publications

(16 citation statements)

References 61 publications

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“…Accordingly, activating microglia or restoring declined microglial number by LPS (even with the dose that is sufficient to cause depression symptoms in naïve animals) or CSF stimulation after weeks of stress exposure reverses depressive behavior (Kreisel et al, 2014;Tong et al, 2017). A recent study further characterized the time window for LPS-stimulated microglia activation in anti-depressive effects (Cai et al, 2020). After 35 days of CUS stimulation, a single dose of LPS can reverse the depressive phenotypes in 5 hours and the effects remain for at least ten days in mice.…”

Section: Declined Microglia In Depressionmentioning

confidence: 99%

Microglia in depression: current perspectives

Jia

Gao

2020

Sci. China Life Sci.

174

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Major depressive disorder (MDD) is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain. Accumulating studies started to reveal that microglia, the primary resident immune cells, play an important role in the development and progression of depression. Microglia respond to stress-triggered neuroinflammation, and through the release of proinflammatory cytokines and their metabolic products, microglia may modulate the function of neurons and astrocytes to regulate depression. In this review, we focused on the role of microglia in the etiology of depression. We discussed the dynamic states of microglia; the correlative and causal evidence of microglial abnormalities in depression; possible mechanisms of how microglia sense depression-related stress and modulate depression state; and how antidepressive therapies affect microglia. Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness.

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Section: Declined Microglia In Depressionmentioning

confidence: 99%

Microglia in depression: current perspectives

Jia

Gao

2020

Sci. China Life Sci.

174

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“…In fact, multiple studies have reported different results regarding the extent of depletion of microglia using PLX3397. While some have found a depletion of around 90% of microglial cells [31,37,38,41], others report depletion rates between 30 and 60% [42][43][44][45]. To the best of our knowledge, complete microglial ablation has never been reported [46].…”

Section: Discussionmentioning

confidence: 81%

“…Pexidartinib (PLX3397), an orally bioavailable selective CSF1R inhibitor that crosses the blood-brain barrier [36], is one of the most widely used CSF1R inhibitors, causing microglial depletion within several days of administration [31,[37][38][39][40], albeit to different extents in different studies. While depletion efficiency varies, full microglial ablation has never been reported [37,38,[41][42][43][44][45]. In fact, it is known that a small subset of microglia in adult mouse brains can survive without CSF1R signaling [46].…”

Section: Introductionmentioning

confidence: 99%

Microglial Depletion Has No Impact on Disease Progression in a Mouse Model of Machado–Joseph Disease

Campos

Duarte‐Silva

Fernandes

et al. 2022

Cells

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Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder (ND). While most research in NDs has been following a neuron-centric point of view, microglia are now recognized as crucial in the brain. Previous work revealed alterations that point to an increased activation state of microglia in the brain of CMVMJD135 mice, a MJD mouse model that replicates the motor symptoms and neuropathology of the human condition. Here, we investigated the extent to which microglia are actively contributing to MJD pathogenesis and symptom progression. For this, we used PLX3397 to reduce the number of microglia in the brain of CMVMJD135 mice. In addition, a set of statistical and machine learning models were further implemented to analyze the impact of PLX3397 on the morphology of the surviving microglia. Then, a battery of behavioral tests was used to evaluate the impact of microglial depletion on the motor phenotype of CMVMJD135 mice. Although PLX3397 treatment substantially reduced microglia density in the affected brain regions, it did not affect the motor deficits seen in CMVMJD135 mice. In addition to reducing the number of microglia, the treatment with PLX3397 induced morphological changes suggestive of activation in the surviving microglia, the microglia of wild-type animals becoming similar to those of CMVMJD135 animals. These results suggest that microglial cells are not key contributors for MJD progression. Furthermore, the impact of PLX3397 on microglial activation should be taken into account in the interpretation of findings of ND modification seen upon treatment with this CSF1R inhibitor.

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“…In this study, we concentrated on the latent curative effect and the underlying neuroimmune mechanisms of Rg1 against depression in vivo and in vitro . Chronic unpredictable stress (CUS) is an internationally recognized method for modeling depression-like behaviors in rats ( Wohleb et al, 2018 ; Cai et al, 2020 ), concomitant with undesirable inflammatory responses ( Zhou et al, 2019 ). Additionally, lipopolysaccharide (LPS)-induced inflammation has been widely used as a model in vitro ( Harland et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rg1 Ameliorates Neuroinflammation via Suppression of Connexin43 Ubiquitination to Attenuate Depression

Wang

Yang

et al. 2021

Front. Pharmacol.

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Depression is an inflammation-associated disease that results in major depression as inflammation increases and progresses. Ginsenoside Rg1 (Rg1), the major bioactive ingredient derived from ginseng, possesses remarkable anti-depressant and anti-inflammatory effects. Our previous studies showed that the pathogenesis of depression was concomitant with the acceleration of connexin43 (Cx43) ubiquitin degradation, while Rg1 could upregulate Cx43 expression to attenuate depression. However, whether the ubiquitination of Cx43 is the specific correlation between depression and inflammation, and how Rg1 ameliorates neuroinflammation to attenuate depression, are still under investigation. In in vivo experiments, Rg1 treatment significantly ameliorated depression-like behaviors in rats subjected to chronic unpredictable stress (CUS). Moreover, these CUS rats treated with Rg1 exhibited attenuated neuroinflammation, together with the suppression of Cx43 ubiquitination. In in vitro experiments, Rg1 reduced the secretion of inflammatory cytokines and the ubiquitination of Cx43 in lipopolysaccharide-induced glial cells. Furthermore, treatment with ubiquitin-proteasome inhibitor MG132 suppressing the ubiquitination of Cx43 ameliorated lipopolysaccharide-induced neuroinflammation. The results suggest that Rg1 attenuates depression-like behavioral performances in CUS-exposed rats; and the main mechanism of the antidepressant-like effects of Rg1 appears to involve protection against neuroinflammation via suppression of Cx43 ubiquitination. In conclusion, Rg1 could ameliorate neuroinflammation via suppression of Cx43 ubiquitination to attenuate depression, which represents the perspective of an innovative therapy of Rg1 in the treatment of inflammation-associated depression.

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Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress

Cited by 32 publications

References 61 publications

Microglia in depression: current perspectives

Microglia in depression: current perspectives

Microglial Depletion Has No Impact on Disease Progression in a Mouse Model of Machado–Joseph Disease

Ginsenoside Rg1 Ameliorates Neuroinflammation via Suppression of Connexin43 Ubiquitination to Attenuate Depression

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