Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition

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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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-03-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-025-07566-2
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Summary: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.
ISSN:2399-3642

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