Language：English   Publisher：Journal of Neurochemistry  

Recent studies have highlighted the potential involvement of reactive oxygen species (ROS) and microglia, a major source of ROS, in the pathophysiology of schizophrenia. In our study, we explored how the second-generation antipsychotic risperidone (RIS) affects ROS regulation and microglial activation in the hippocampus using a mouse ketamine (KET) model of schizophrenia. KET administration resulted in schizophrenia-like behaviors in male C57BL/6J mice, such as impaired prepulse inhibition (PPI) of the acoustic startle response and hyper-locomotion. These behaviors were mitigated by RIS. We found that the gene expression level of an enzyme responsible for ROS production (Nox2), which is primarily associated with activated microglia, was lower in KET/RIS-treated mice than in KET-treated mice. Conversely, the levels of antioxidant enzymes (Ho-1 and Gclc) were higher in KET/RIS-treated mice. The microglial density in the hippocampus was increased in KET-treated mice, which was counteracted by RIS. Hierarchical cluster analysis revealed three morphological subtypes of microglia. In control mice, most microglia were resting-ramified (type I, 89.7%). KET administration shifted the microglial composition to moderately ramified (type II, 44.4%) and hyper-ramified (type III, 25.0%). In KET/RIS-treated mice, type II decreased to 32.0%, while type III increased to 34.0%. An in vitro ROS assay showed that KET increased ROS production in dissociated hippocampal microglia, and this effect was mitigated by RIS. Furthermore, we discovered that a NOX2 inhibitor could counteract KET-induced behavioral deficits. These findings suggest that pharmacological inhibition of ROS production by RIS may play a crucial role in ameliorating schizophrenia-related symptoms. Moreover, modulating microglial activation to regulate ROS production has emerged as a novel avenue for developing innovative treatments for schizophrenia. (Figure presented.).

DOI： 10.1111/jnc.16133

Web of Science

Scopus

PubMed

Language：English   Publisher：Molecular Brain  

CD11c-positive (CD11c+) microglia have attracted considerable attention because of their potential implications in central nervous system (CNS) development, homeostasis, and disease. However, the spatiotemporal dynamics of the proportion of CD11c+ microglia in individual CNS regions are poorly understood. Here, we investigated the proportion of CD11c+ microglia in six CNS regions (forebrain, olfactory bulb, diencephalon/midbrain, cerebellum, pons/medulla, and spinal cord) from the developmental to adult stages by flow cytometry and immunohistochemical analyses using a CD11c reporter transgenic mouse line, Itgax-Venus. We found that the proportion of CD11c+ microglia in total microglia varied between CNS regions during postnatal development. Specifically, the proportion was high in the olfactory bulb and cerebellum at postnatal day P(4) and P7, respectively, and approximately half of the total microglia were CD11c+. The proportion declined sharply in all regions to P14, and the low percentage persisted over P56. In the spinal cord, the proportion of CD11c+ microglia was also high at P4 and declined to P14, but increased again at P21 and thereafter. Interestingly, the distribution pattern of CD11c+ microglia in the spinal cord markedly changed from gray matter at P4 to white matter at P21. Collectively, our findings reveal the differences in the spatiotemporal dynamics of the proportion of CD11c+ microglia among CNS regions from early development to adult stages in normal mice. These findings improve our understanding of the nature of microglial heterogeneity and its dynamics in the CNS.

DOI： 10.1186/s13041-024-01098-2

Web of Science

Scopus

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Other Link： https://www.fujifoundation.or.jp/search/pdf/041/41_15.pdf

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Other Link： https://doi.org/10.1152/ajpendo.00035.2018

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jep.2017.12.025

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2017.10.133

Language：English   Publishing type：Research paper (scientific journal)  

Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E₂ type 4 receptor–associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20^+/− onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20^+/−EPRAP^+/+ and J20^+/−EPRAP^−/− mice. EPRAP deficiency reversed the reduced anxiety of J20^+/− mice but did not affect hyperactivity. No differences in spatial memory were observed between J20^+/−EPRAP^+/+ and J20^+/−EPRAP^−/− mice. In comparison with J20^+/−EPRAP^+/+, J20^+/−EPRAP^−/− mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-β 40 or 42 in the cortex and hippocampus. J20^+/−EPRAP^−/− mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20^+/−EPRAP^+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD.

DOI： 10.1016/j.ajpath.2017.04.010

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1161/JAHA.116.004777

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2017.03.095

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1254/fpj.150.114

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4049/jimmunol.1502618

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ajpath.2016.04.002

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.5551/jat.29074

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0136304

Language：English   Publishing type：Research paper (scientific journal)  

Prostaglandin E₂ plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4–associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP-deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis.

DOI： 10.1371/journal.pgen.1005542

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.11339/jtm.30.164

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1254/jphs.11013FP

Event date： 2023.9

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Event date： 2023.9

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Event date： 2023.3

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2022.12

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Event date： 2022.3

Presentation type：Symposium, workshop panel (public)  

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Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2021.10

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Event date： 2021.7

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Venue：神戸   Country：Japan  

Event date： 2021.5

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Event date： 2020.10

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Event date： 2019.11

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Event date： 2019.3

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Venue：新潟   Country：Japan  

Event date： 2018.12

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Event date： 2018.10

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Venue：佐賀大学   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2018.8

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Country：Japan  

Event date： 2018.7

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Country：Japan  

Event date： 2017.3

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Country：Japan  

Event date： 2017.3

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Country：Japan  

Event date： 2016.3

Language：Japanese  

Country：Japan  

Event date： 2015.10

Language：Japanese  

Country：United States  

Event date： 2015.3

Language：Japanese  

Country：Japan  

Event date： 2014.11

Language：Japanese  

Country：United States  

Event date： 2013.6

Language：Japanese  

Country：Japan  

Event date： 2011.8

Language：Japanese  

Country：Japan  

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