Maternal Immune Activation (MIA) is a phenomenon of pathophysiological stimulation of the maternal immune system during gestation which potentially leads to functional and structural disturbances of fetal neurogenesis. It occurs due to the alteration of paracrine signals between the maternal organism and the developing nervous system of the fetus. Any disturbances in the brain at embryonic and early postnatal stages might compromise its natural developmental trajectory, which could potentially increase the risk of developing neuropsychiatric disorders, such as schizophrenia, autistic spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), major depressive and bipolar disorders, etc. Presumably, all these conditions could initiate the development of age-related cognitive impairment in late ontogenesis, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. As the main immune cell population in the CNS, microglia both mediate its proper development and receive pathological stimuli from the maternal organism. This could lead to microglia premature activation and could become a part of the mechanisms of the fetal CNS development alterations. In this review, we discuss the role of prenatal activation of microglia in neuropsychiatric disorders and neurodegenerative disease development. We highlight approaches to modeling MIA, as well as sex differences in the morphological and functional state of microglia in the context of physiological conditions. There is a hypothesis discussed regarding the contribution of these distinctions to neuropsychiatric disorders and neurodegenerative disease incidence, prevalence, and progression in males and females.

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.