Maternal Immune Activation Leads to Lasting Sex-Specific Changes in Behavior and Hippocampal Morphological and Molecular Features in 12-Month-Old Rat Offspring

Maternal immune activation (MIA) during pregnancy is a recognized risk factor for neurodevelopmental and neurodegenerative disorders, including Alzheimer’s disease. Although the long-term consequences of prenatal inflammation have been extensively investigated, the influence of biological sex on age-related behavioral and hippocampal alterations remains insufficiently understood. MIA was induced in pregnant Wistar rats by the intraperitoneal administration of lipopolysaccharide (100 μg/kg) on gestational day 17. Male and female offspring were examined at 12 months of age. Behavioral patterns were assessed using the Morris water maze and elevated plus maze. Hippocampal neuronal morphology and microglial and astrocytic phenotypes were evaluated by histology and IHC, while the expression of genes associated with inflammation, neurodegeneration, neuroplasticity, oxidative stress, and neurogenesis was determined by RT-qPCR. Prenatal LPS exposure produced persistent behavioral alterations in both sexes but with distinct phenotypes. Both male and female offspring exhibited increased anxiety-like behavior, whereas females showed reduced exploratory activity during spatial memory testing. Female offspring demonstrated more pronounced hippocampal pathology, including an increased relative number of pyknotic hyperchromic neurons, a reduced ramified-to-amoeboid microglia ratio, decreased Bdnf, and selective upregulation of Bace1 and Usp11, potentially indicating enhanced susceptibility to neurodegenerative processes. In contrast, males maintained predominantly ramified microglia morphology and showed increased expression of the neuronal progenitor gene Pax6, possibly suggesting the activation of compensatory mechanisms. Both sexes exhibited hippocampal upregulation of Il18, Arg1, Mmp9, Ntrk2, and Gpx4, consistent with chronic pro-inflammatory background accompanied by adaptive antioxidant and anti-inflammatory responses. Prenatal immune activation induces long-lasting behavioral, morphological, and molecular alterations that persist into middle age and exhibit marked sexual dimorphism. Female offspring appear more vulnerable to pro-neurodegenerative changes, whereas male offspring activate compensatory neuroprotective pathways that might partially preserve hippocampal function despite sustained pro-inflammatory reactions. These findings highlight sex as a critical biological variable in the long-term consequences of prenatal inflammation and may facilitate the identification of early biomarkers and therapeutic targets for MIA-associated neuropsychiatric and neurodegenerative disorders.