Maternal Immune Activation Causes Schizophrenia-like Behaviors in the Offspring through Activation of Immune-Inflammatory, Oxidative and Apoptotic Pathways, and Lowered Antioxidant Defenses and Neuroprotection

Schizophrenia is a complex neuropsychiatric disorder, influenced by a combined action of genes and environmental factors. The neurodevelopmental origin is one of the most widely recognized etiological models of this heterogeneous disorder. Environmental factors, especially infections during gestation, appear to be a major risk determinant of neurodevelopmental basis of schizophrenia. Prenatal infection may cause maternal immune activation (MIA) and enhance risk of schizophrenia in the offspring. However, the precise mechanistic basis through which MIA causes long-lasting schizophrenia-like behavioral deficits in offspring remains inadequately understood. Herein, we aimed to delineate whether prenatal infection-induced MIA causes schizophrenia-like behaviors through its long-lasting effects on immune-inflammatory and apoptotic pathways, oxidative stress toxicity, and antioxidant defenses in the brain of offspring. Sprague-Dawley rats were divided into three groups (n = 15/group) and were injected with poly (I:C), LPS, and saline at gestational day (GD)-12. Except IL-1 beta, plasma levels of IL-6, TNF-alpha, and IL-17A assessed after 24 h were significantly elevated in both the poly (I:C)- and LPS-treated pregnant rats, indicating MIA. The rats born to dams treated with poly (I:C) and LPS displayed increased anxiety-like behaviors and significant deficits in social behaviors. Furthermore, the hippocampus of the offspring rats of both the poly (I:C)- and LPS-treated groups showed increased signs of lipid peroxidation, diminished total antioxidant content, and differentially upregulated expression of inflammatory (TNF alpha, IL6, and IL1 beta), and apoptotic (Bax, Cas3, and Cas9) genes but decreased expression of neuroprotective (BDNF and Bcl2) genes. The results suggest long-standing effects of prenatal infections on schizophrenia-like behavioral deficits, which are mediated by immune-inflammatory and apoptotic pathways, increased oxidative stress toxicity, and lowered antioxidant and neuroprotective defenses. The findings suggest that prenatal infections may underpin neurodevelopmental aberrations and neuroprogression and subsequently schizophrenia-like symptoms.