Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition
Abstract The functional alteration of microglia arises in brains exposed to external stress during early development. Pathophysiological findings of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder suggest cerebellar functional deficits. However, the link between stres...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07566-2 |
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| author | Momoka Hikosaka Md Sorwer Alam Parvez Yuki Yamawaki Souichi Oe Yuan Liang Yayoi Wada Yukie Hirahara Taro Koike Hirohiko Imai Naoya Oishi Sina M. Schalbetter Asuka Kumagai Mari Yoshida Takeshi Sakurai Masaaki Kitada Urs Meyer Shuh Narumiya Gen Ohtsuki |
| author_facet | Momoka Hikosaka Md Sorwer Alam Parvez Yuki Yamawaki Souichi Oe Yuan Liang Yayoi Wada Yukie Hirahara Taro Koike Hirohiko Imai Naoya Oishi Sina M. Schalbetter Asuka Kumagai Mari Yoshida Takeshi Sakurai Masaaki Kitada Urs Meyer Shuh Narumiya Gen Ohtsuki |
| author_sort | Momoka Hikosaka |
| collection | DOAJ |
| description | Abstract The functional alteration of microglia arises in brains exposed to external stress during early development. Pathophysiological findings of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder suggest cerebellar functional deficits. However, the link between stress-induced microglia reactivity and cerebellar dysfunction is missing. Here, we investigate the developmental immune environment in translational mouse models that combine two risk factors: maternal infection and repeated social defeat stress (2HIT). We find the synergy of inflammatory stress insults, leading to microglial increase specifically in the cerebellum of both sexes. Microglial turnover correlates with the Purkinje neuron loss in 2HIT mice. Highly multiplexed imaging-mass-cytometry identifies a cell transition to TREM2(+) stress-associated microglia in the cerebellum. Single-cell-proteomic clustering reveals IL-6- and TGFβ-signaling association with microglial cell transitions. Reduced excitability of remaining Purkinje cells, cerebellum-involved brain-wide functional dysconnectivity, and behavioral abnormalities indicate cerebellar cognitive dysfunctions in 2HIT animals, which are ameliorated by both systemic and cerebellum-specific microglia replacement. |
| format | Article |
| id | doaj-art-961a5548bd7241598a805e4eccd1cc1f |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-961a5548bd7241598a805e4eccd1cc1f2025-08-20T01:57:48ZengNature PortfolioCommunications Biology2399-36422025-03-018112610.1038/s42003-025-07566-2Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognitionMomoka Hikosaka0Md Sorwer Alam Parvez1Yuki Yamawaki2Souichi Oe3Yuan Liang4Yayoi Wada5Yukie Hirahara6Taro Koike7Hirohiko Imai8Naoya Oishi9Sina M. Schalbetter10Asuka Kumagai11Mari Yoshida12Takeshi Sakurai13Masaaki Kitada14Urs Meyer15Shuh Narumiya16Gen Ohtsuki17Department of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineDepartment of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineDepartment of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineDepartment of Anatomy, Kansai Medical UniversityDepartment of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineDepartment of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineDepartment of Anatomy, Kansai Medical UniversityDepartment of Anatomy, Kansai Medical UniversityDepartment of Systems Science, Kyoto University Graduate School of Informatics, Yoshida-HonmachiDepartment of Psychiatry, Kyoto University Graduate School of MedicineInstitute of Veterinary Pharmacology and Toxicology, University of ZurichStandard BioTools Inc.Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical UniversityDepartment of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineDepartment of Anatomy, Kansai Medical UniversityInstitute of Veterinary Pharmacology and Toxicology, University of ZurichDepartment of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineDepartment of Drug Discovery Medicine, Kyoto University, Graduate School of MedicineAbstract The functional alteration of microglia arises in brains exposed to external stress during early development. Pathophysiological findings of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder suggest cerebellar functional deficits. However, the link between stress-induced microglia reactivity and cerebellar dysfunction is missing. Here, we investigate the developmental immune environment in translational mouse models that combine two risk factors: maternal infection and repeated social defeat stress (2HIT). We find the synergy of inflammatory stress insults, leading to microglial increase specifically in the cerebellum of both sexes. Microglial turnover correlates with the Purkinje neuron loss in 2HIT mice. Highly multiplexed imaging-mass-cytometry identifies a cell transition to TREM2(+) stress-associated microglia in the cerebellum. Single-cell-proteomic clustering reveals IL-6- and TGFβ-signaling association with microglial cell transitions. Reduced excitability of remaining Purkinje cells, cerebellum-involved brain-wide functional dysconnectivity, and behavioral abnormalities indicate cerebellar cognitive dysfunctions in 2HIT animals, which are ameliorated by both systemic and cerebellum-specific microglia replacement.https://doi.org/10.1038/s42003-025-07566-2 |
| spellingShingle | Momoka Hikosaka Md Sorwer Alam Parvez Yuki Yamawaki Souichi Oe Yuan Liang Yayoi Wada Yukie Hirahara Taro Koike Hirohiko Imai Naoya Oishi Sina M. Schalbetter Asuka Kumagai Mari Yoshida Takeshi Sakurai Masaaki Kitada Urs Meyer Shuh Narumiya Gen Ohtsuki Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition Communications Biology |
| title | Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition |
| title_full | Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition |
| title_fullStr | Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition |
| title_full_unstemmed | Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition |
| title_short | Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition |
| title_sort | maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition |
| url | https://doi.org/10.1038/s42003-025-07566-2 |
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