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Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation


Weber-Stadlbauer, Ulrike; Richetto, Juliet; Zwamborn, Ramona A J; Slieker, Roderick C; Meyer, Urs (2021). Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation. Neuropsychopharmacology, 46(2):404-412.

Abstract

Prenatal exposure to infectious and/or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components. Recent research using animal models suggests that maternal immune activation (MIA) can induce transgenerational effects on brain and behavior, possibly through epigenetic mechanisms. Using a mouse model of MIA that is based on gestational treatment with the viral mimeticpoly(I:C) (= <jats:italic>polyriboinosinic-polyribocytidilic</jats:italic> acid), the present study explored whether the transgenerational effects of MIA are extendable to dopaminergic dysfunctions. We show that the direct descendants born to poly(I:C)-treated mothers display signs of hyperdopaminergia, as manifested by a potentiated sensitivity to the locomotor-stimulating effects of amphetamine (Amph) and increased expression of tyrosine hydroxylase (<jats:italic>Th</jats:italic>) in the adult ventral midbrain. In stark contrast, second- and third-generation offspring of MIA-exposed ancestors displayed blunted locomotor responses to Amph and reduced expression of <jats:italic>Th</jats:italic>. Furthermore, we found increased DNA methylation at the promoter region of the dopamine-specifying factor, nuclear receptor-related 1 protein (<jats:italic>Nurr1</jats:italic>), in the sperm of first-generation MIA offspring and in the ventral midbrain of second-generation offspring of MIA-exposed ancestors. The latter effect was further accompanied by reduced mRNA levels of Nurr1 in this brain region. Together, our results suggest that MIA has the potential to modify dopaminergic functions across multiple generations with opposite effects in the direct descendants and their progeny. The presence of altered DNA methylation in the sperm of MIA-exposed offspring highlights the possibility that epigenetic processes in the male germline play a role in the transgenerational effects of MIA.

Abstract

Prenatal exposure to infectious and/or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components. Recent research using animal models suggests that maternal immune activation (MIA) can induce transgenerational effects on brain and behavior, possibly through epigenetic mechanisms. Using a mouse model of MIA that is based on gestational treatment with the viral mimeticpoly(I:C) (= <jats:italic>polyriboinosinic-polyribocytidilic</jats:italic> acid), the present study explored whether the transgenerational effects of MIA are extendable to dopaminergic dysfunctions. We show that the direct descendants born to poly(I:C)-treated mothers display signs of hyperdopaminergia, as manifested by a potentiated sensitivity to the locomotor-stimulating effects of amphetamine (Amph) and increased expression of tyrosine hydroxylase (<jats:italic>Th</jats:italic>) in the adult ventral midbrain. In stark contrast, second- and third-generation offspring of MIA-exposed ancestors displayed blunted locomotor responses to Amph and reduced expression of <jats:italic>Th</jats:italic>. Furthermore, we found increased DNA methylation at the promoter region of the dopamine-specifying factor, nuclear receptor-related 1 protein (<jats:italic>Nurr1</jats:italic>), in the sperm of first-generation MIA offspring and in the ventral midbrain of second-generation offspring of MIA-exposed ancestors. The latter effect was further accompanied by reduced mRNA levels of Nurr1 in this brain region. Together, our results suggest that MIA has the potential to modify dopaminergic functions across multiple generations with opposite effects in the direct descendants and their progeny. The presence of altered DNA methylation in the sperm of MIA-exposed offspring highlights the possibility that epigenetic processes in the male germline play a role in the transgenerational effects of MIA.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Pharmacology
Health Sciences > Psychiatry and Mental Health
Uncontrolled Keywords:Pharmacology, Psychiatry and Mental health
Language:English
Date:1 January 2021
Deposited On:19 Feb 2021 15:42
Last Modified:20 Feb 2021 21:00
Publisher:Nature Publishing Group
ISSN:0893-133X
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41386-020-00855-w

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