Bibliographic Details
| Title: |
Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition. |
| Authors: |
Hikosaka, Momoka, Parvez, Md Sorwer Alam, Yamawaki, Yuki, Oe, Souichi, Liang, Yuan, Wada, Yayoi, Hirahara, Yukie, Koike, Taro, Imai, Hirohiko, Oishi, Naoya, Schalbetter, Sina M., Kumagai, Asuka, Yoshida, Mari, Sakurai, Takeshi, Kitada, Masaaki, Meyer, Urs, Narumiya, Shuh, Ohtsuki, Gen |
| Source: |
Communications Biology; 3/3/2025, Vol. 8 Issue 1, p1-26, 26p |
| Subject Terms: |
SOCIAL defeat, MATERNAL immune activation, PURKINJE cells, SCHIZOPHRENIA, DISEASE risk factors, CEREBELLAR cortex |
| 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. Early developmental stress alters microglial function, linked to schizophrenia and autism. In a mouse model, inflammatory 2HIT stress increased cerebellar microglia and its turnover, causing Purkinje neuron loss and cerebellar dysfunction, which was improved by microglia replacement. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
