The Role of Prenatal Microglial Activation and Its Sex Differences in the Development of Neuropsychiatric Disorders and Neurodegenerative Diseases

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. © 2025 Elsevier B.V., All rights reserved.