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.