System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish 5 citations

PubMed: 40033126 DOI: 10.1038/s42003-025-07566-2

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

Commun Biol 8(1):296

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

Affiliations

  • Department of Drug Discovery Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
  • Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Department of Anatomy, Kansai Medical University, Hirakata-shi, Osaka, Japan.
  • Department of Drug Discovery Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan. Institute of Basic Theory in Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
  • Department of Systems Science, Kyoto University Graduate School of Informatics, Yoshida-Honmachi, Kyoto, Japan.
  • Innovation Research Center for Quantum Medicine, Gifu University School of Medicine, Gifu, Japan.
  • Department of Psychiatry, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Institute of Veterinary Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
  • Standard BioTools Inc. Chuo-ku, Tokyo, Japan.
  • Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Aichi, Japan.
  • Department of Drug Discovery Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan.

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.

MeSH

Microglia, Cells, Biological Science Disciplines, Stress, Physiological, Brain, Cerebellum, Purkinje Cells, Cognition