Maternal immune activation primes adult offspring for insult-dependent Parkinsonian vulnerability in male mice

Maternal immune activation (MIA) can persistently alter offspring neuroimmune functions, but its contribution to the susceptibility to neurodegenerative diseases remains unclear. We tested whether Poly(I:C)-induced MIA enhances a latent vulnerability to mechanistically distinct PD-related insults. Single-cell RNA sequencing of adult offspring's brain revealed broadly preserved cellular composition but identified a disease-relevant transcriptional signature centered on astrocytes.

Astrocytic differentially expressed genes were enriched for Parkinson's disease and broader neurodegenerative pathways, suggesting that MIA programs an adult astrocyte-linked susceptibility state. Consistent with this indication, MIA offspring challenged with MPTP developed exacerbated motor deficits, greater loss of dopaminergic neurons in the nigrostriatal system, and enhanced GFAP+ astrocyte reactivity. MIA offspring challenged with α-synuclein preformed fibrils (PFF) also showed worsened motor dysfunction and dopaminergic injury, but without a detectable increase in GFAP+ astrocyte density.

Thus, MIA establishes a latent vulnerability that is revealed by later PD-related injury rather than directly causing adult Parkinsonism. The expression of this vulnerability is insult-dependent. These findings identify developmental immune programming as a modifier of adult nigrostriatal resilience and implicate astrocyte-linked molecular states as a disease primer between early-life inflammation and later neurodegenerative risk.

We thank all members in the Zhou lab, Le lab, and Bi lab for assistance. This research was funded by National Science and Technology Major Project (2025ZD0216202 to Z.Z.), Department of Science and Technology of Guangdong Province (2024TX08A283 to Z.Z.), Science and Technology Commission of Shanghai Municipal (24ZR1477800 to Z.Z.), National Natural Science Foundation of China (82174158 to Y.B.), The Healthcare Talents Elite Program of Shanghai Pudong New Area (2025PDWSYCBJ-07 to Y.B.) and Zhongshan Municipal Bureau of Science and Technology (CXTD2022013 to Z.Z.). These authors contributed equally: Chao Pan, Liting Wen, Qingcheng Dai, Kaikai Jin, Guijiang Liu.

Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China Chao Pan, Weili Luo, Mengxue Gu, Yuping Li, Xiaoyun Zhang, Xiaolin Zhang, Xinglong Liu & Zikai Zhou Nanjing University of Chinese Medicine, Nanjing, China Liting Wen, Qingcheng Dai, Kaikai Jin & Zikai Zhou Southern Medical University, Guangzhou, China Zhoupu Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China University of Chinese Academy of Sciences, Beijing, China Correspondence to Weidong Le, Yong Bi or Zikai Zhou. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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