title: Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments.
abstract: Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions. In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations in Nurr1, a transcription factor highly essential for normal dopaminergic development. We combined a mouse model of heterozygous genetic deletion of Nurr1 with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene-environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems. Our findings provide evidence for specific gene-environment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamine-associated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes.
authors.affiliation: Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, 8603 Schwerzenbach, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Vuillermot
authors.forename: Eliza
authors.initials: E
authors.lastname: Joodmardi
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlmann
authors.forename: Sven Ove
authors.initials: SO
authors.lastname: Ögren
authors.forename: Joram
authors.initials: J
authors.lastname: Feldon
authors.forename: Urs
authors.initials: U
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000276:immunology* / Q000821:virology; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019965:Neurocognitive Disorders / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000172:deficiency / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012559:Schizophrenia / Q000235:genetics / Q000276:immunology / Q000821:virology; D014777:Virus Diseases / Q000150:complications / Q000276:immunology
chemical_list: D057126:Nuclear Receptor Subfamily 4, Group A, Member 2