Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Xia, Yucen; Zhang, Zhiqing; Lin, Wei-Peng; Yan, Jun; Zhu, Caixia; Yin, Dong-Min; Su, He; Su, Yang; Xu, Nenggui; Caldwell, Robert W.; Yao, Lin; Chen, Yongjun

doi:10.1038/s41386-020-0743-7

Cited by 38 publications

(33 citation statements)

References 87 publications

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“…IL4-induced Arg1 + microglia can be thought of a special phenotype of beneficial microglia ( 21 , 30 ). These cells regulate inflammatory processes in the brain and enhance neurite growth, thereby exhibiting neuroprotective effects ( 20 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

“…IL4 deficiency weakens the resilience against stress-induced depression, while increasing IL4 levels can alleviate depressive-like behaviors ( 18 , 19 ). Studies have shown that IL4 can reprogram microglia toward an Arg1 + phenotype for maintaining brain homeostasis, neuroprotection, and tissue repair ( 20 , 21 ). However, the effects of IL4-induced Arg1 + microglia on neurogenesis and stress resilience are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

et al. 2021

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Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific microglia groups and functionally implicated in behavioral responses to stress. However, the role of microglia in hippocampal neurogenesis and stress resilience remains unclear. We identified interleukin 4 (IL4)–driven microglia characterized by high expression of Arg1, which is critical in maintaining hippocampal neurogenesis and stress resistance. Decreasing Arg1+ microglia in the hippocampus by knocking down the microglial IL4R suppressed hippocampal neurogenesis and enhanced stress vulnerability. Increasing Arg1+ microglia in the hippocampus by enhancing IL4 signaling restored hippocampal neurogenesis and the resilience to stress-induced depression. Brain-derived neurotrophic factor (BDNF) was found necessary for the proneurogenesis effects of IL4-driven microglia. Together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis responding to chronic stress, helping protect against depressive-like symptoms. These findings identify the modulation of a specific microglial phenotype as a treatment strategy for mood disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

et al. 2021

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“…MIA produces an increase in pro-inflammatory cytokines and MMP-9 release in the fetal body, both of which are inducers of microglial activity [ 28 ]. Prenatal infections and MIA are furthermore associated with microglial overactivation in children [ 31 ]. Interestingly, prenatal infections have recently been reported to cause astrocytes to react in a hypersensitive manner to stimuli in the future [ 32 ].…”

Section: Environmental Factors Implicated In Synaptic Pruningmentioning

confidence: 99%

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

Germann

Brederoo²,

Sommer

2021

Current Opinion in Psychiatry

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Purpose of review Excessive synaptic pruning has first been suggested by Irwin Feinberg (1982) as an important pillar in the pathophysiology in schizophrenia (SCZ). This article reviews recent developments highlighting factors implicated in aberrant synaptic pruning and its contribution to disease onset and emergence of cognitive symptoms in SCZ. Unraveling these factors provides new insights for potential prevention and treatment strategies for psychotic disorders. Recent findings Increased pruning in SCZ was recently confirmed by a positron emission tomography-study employing the novel tracer [11C]UCB-J, demonstrating the consequential loss of synaptic density. Recent evidence supports the contributing role of astrocytes and increased complement-mediated microglial pruning in disease onset and cognitive symptoms in SCZ. Increased microglial pruning is mediated specifically by C4. Furthermore, environmental factors (e.g., infections and stress) can lead to dysbiosis which was recently linked to microglial activation and pruning in SCZ. Summary Recent findings render the pruning machinery a potential target for early treatment and prevention in individuals at high risk for SCZ. Minocycline can improve cognition in SCZ, probably by reducing excessive pruning. Probiotics might also have beneficial effects on cognition, although recent findings are not encouraging. N-acetyl-cysteine recovers functional connectivity in SCZ both in vitro and in vivo, making it an interesting candidate.

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“…Tamoxifen administration was performed as we previously described [ 31 ]. Myh6-CreER mice were crossed with ARG 2 f/f mice to get Myh6-CreER; ARG 2 loxp/loxp (Myh6-ARG 2-/-).…”

Section: Methodsmentioning

confidence: 99%

Protection against Doxorubicin‐Induced Cardiotoxicity through Modulating iNOS/ARG 2 Balance by Electroacupuncture at PC6

Wang

Yao

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Doxorubicin (DOX) is a commonly used chemotherapeutic drug but is limited in clinical applications by its cardiotoxicity. Neiguan acupoint (PC6) is a well-recognized acupoint for the treatment of cardiothoracic disease. However, whether acupuncture at PC6 could be effective in preventing DOX-induced cardiotoxicity is still unknown. Methods. A set of experiments were performed with myocardial cells, wild type, inducible nitric oxide synthase knockout (iNOS-/-), and myocardial-specific ablation arginase 2 (Myh6-ARG 2-/-) mice. We investigated the protective effect and the underlying mechanisms for electroacupuncture (EA) against DOX-induced cardiotoxicity by echocardiography, immunostaining, biochemical analysis, and molecular biotechnology in vivo and in vitro analysis. Results. We found that DOX-mediated nitric oxide (NO) production was positively correlated with the iNOS level but has a negative correlation with the arginase 2 (ARG 2) level in both myocardial cells and tissues. Meanwhile, EA at PC6 alleviated cardiac dysfunction and cardiac hypertrophy in DOX-treated mice. EA at PC6 blocked the upregulation of NO production in accompanied with the downregulated iNOS and upregulated ARG 2 levels in myocardial tissue induced by DOX. Furthermore, knockout iNOS prevented cardiotoxicity and EA treatment did not cause the further improvement of cardiac function in iNOS-/- mice treated by DOX. In contrast, deficiency of myocardial ARG 2 aggravated DOX-induced cardiotoxicity and reduced EA protective effect. Conclusion. These results suggest that EA treatment at PC6 can prevent DOX-induced cardiotoxicity through modulating NO production by modulating the iNOS/ARG 2 balance in myocardial cells.

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Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Cited by 38 publications

References 87 publications

IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

Protection against Doxorubicin‐Induced Cardiotoxicity through Modulating iNOS/ARG 2 Balance by Electroacupuncture at PC6

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