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Maternal Vitamin D Prevents Abnormal Dopaminergic Development and Function in a Mouse Model of Prenatal Immune Activation.

ABSTRACT: Dysfunction in dopamine (DA) systems is a prominent feature in schizophrenia patients and may result from the abnormal development of mesencephalic (mes)DA systems. Maternal immune activation (MIA) and developmental vitamin D (DVD)-deficiency both induce schizophrenia-relevant dopaminergic abnormalities in adult offspring. In this study, we investigated whether maternal administration of the vitamin D hormone (1,25OHD, VIT_D) could prevent MIA-induced abnormalities in DA-related behaviors and mesDA development. We administrated the viral mimetic polyriboinosinic-polyribocytidylic (poly (I:C)) simultaneously with 1,25OHD and/or their vehicles, to pregnant mouse dams at gestational day 9. Maternal treatment with VIT_D prevented MIA-induced hypersensitivity to acute DA stimulation induced by amphetamine, whereas it failed to block prepulse inhibition deficiency in MIA-exposed offspring. MIA and VIT_D both reduced fetal mesDA progenitor (Lmx1a?+?Sox2+) cells, while VIT_D treatment increased the number of mature (Nurr1?+?TH+) mesDA neurons. Single-cell quantification of protein expression showed that VIT_D treatment increased the expression of Lmx1a, Nurr1 and TH in individual mesDA cells and restored normal mesDA positioning. Our data demonstrate that VIT_D prevents abnormal dopaminergic phenotypes in MIA offspring possibly via its early neuroprotective actions on fetal mesDA neurons. Maternal supplementation with the dietary form of vitamin D, cholecalciferol may become a valuable strategy for the prevention of MIA-induced neurodevelopmental abnormalities.

SUBMITTER: Luan W

PROVIDER: S-EPMC6021387 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Maternal Vitamin D Prevents Abnormal Dopaminergic Development and Function in a Mouse Model of Prenatal Immune Activation.

Luan Wei W Hammond Luke Alexander LA Vuillermot Stephanie S Meyer Urs U Eyles Darryl Walter DW

Scientific reports 20180627 1

Dysfunction in dopamine (DA) systems is a prominent feature in schizophrenia patients and may result from the abnormal development of mesencephalic (mes)DA systems. Maternal immune activation (MIA) and developmental vitamin D (DVD)-deficiency both induce schizophrenia-relevant dopaminergic abnormalities in adult offspring. In this study, we investigated whether maternal administration of the vitamin D hormone (1,25OHD, VIT<sub>D</sub>) could prevent MIA-induced abnormalities in DA-related behavi ...[more]

PMID: 29950608

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Project description:Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.

Dataset Information

Maternal Vitamin D Prevents Abnormal Dopaminergic Development and Function in a Mouse Model of Prenatal Immune Activation.

Publications

Maternal Vitamin D Prevents Abnormal Dopaminergic Development and Function in a Mouse Model of Prenatal Immune Activation.

Similar Datasets

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