title: Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging.
abstract: BACKGROUND
  Prenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pregnancy.
  
  
  METHODS
  Pregnant C57BL6/J mice on gestation day 17 were treated with the viral mimetic polyriboinosinic-polyribocytidilic acid (poly(I:C)) or control vehicle solution. The resulting offspring were first tested using cognitive and behavioral paradigms known to be sensitive to hippocampal damage, after which they were assigned to quantitative analyses of inflammatory cytokines, microglia density and morphology, astrocyte density, presynaptic markers, and neurotrophin expression in the hippocampus throughout aging (1, 5, and 22 months of age).
  
  
  RESULTS
  Maternal poly(I:C) treatment led to a robust increase in inflammatory cytokine levels in late gestation but did not cause persistent systemic or hippocampal inflammation in the offspring. The late prenatal manipulation also failed to cause long-term changes in microglia density, morphology, or activation, and did not induce signs of astrogliosis in pubescent, adult, or aged offspring. Despite the lack of persistent inflammatory or glial anomalies, offspring of poly(I:C)-exposed mothers showed marked and partly age-dependent deficits in hippocampus-regulated cognitive functions as well as impaired hippocampal synaptophysin and brain-derived neurotrophic factor (BDNF) expression.
  
  
  CONCLUSIONS
  Late prenatal exposure to viral-like immune activation in mice causes hippocampus-related cognitive and synaptic deficits in the absence of chronic inflammation across aging. These findings do not support the hypothesis that this form of prenatal immune activation may induce pathological brain aging via sustained effects on systemic and central inflammation. We further conclude that poly(I:C)-based prenatal immune activation models are reliable in their effectiveness to induce (hippocampal) neuropathology across aging, but they appear unsuited for studying the role of chronic systemic or central inflammation in brain aging.
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Giovanoli
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Notter
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland.
authors.forename: Juliet
authors.initials: J
authors.lastname: Richetto
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Labouesse
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Vuillermot
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.|Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland. urs.meyer@vetpharm.uzh.ch.|Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland. urs.meyer@vetpharm.uzh.ch.
authors.forename: Urs
authors.initials: U
authors.lastname: Meyer
mesh_terms: D000375:Aging / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D018836:Inflammation Mediators