title: Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies.
abstract: Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1β levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation.
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Giovanoli
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Weber-Stadlbauer
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland. Electronic address: urs.meyer@vetpharm.uzh.ch.
authors.forename: Urs
authors.initials: U
authors.lastname: Meyer
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
mesh_terms: D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000276:immunology* / Q000503:physiopathology*; D007155:Immunologic Factors / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology* / Q000503:physiopathology*
chemical_list: C587672:IL1B protein, mouse; D007155:Immunologic Factors; D053583:Interleukin-1beta; D011070:Poly I-C
keywords: Autism; Cytokines; Inflammation; Maternal immune activation; Microglia; Poly(I:C); Schizophrenia; Synapse