Full-length Article Maternal viral infection during pregnancy elicits anti-social behavior in neonatal piglet offspring independent of postnatal microglial cell activation Adrienne M. Antonson a,b , Emily C. Radlowski a,b , Marcus A. Lawson a,b,c , Jennifer L. Rytych a,b , Rodney W. Johnson a,b,c,d,⇑ a Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA b Integrative Immunology and Behavior Program, University of Illinois Urbana-Champaign, Urbana, IL, USA c Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, IL, USA d Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA article info Article history: Received 28 June 2016 Received in revised form 31 August 2016 Accepted 16 September 2016 Available online xxxx Keywords: Prenatal Maternal immune activation Microglia Cytokines Social behavior Piglet abstract Maternal infection during pregnancy increases risk for neurodevelopmental disorders and reduced stress resilience in offspring, but the mechanisms are not fully understood. We hypothesized that piglets born from gilts infected with a respiratory virus during late gestation would exhibit aberrant microglia activ- ity, cognitive deficits and reduced sociability. Pregnant gilts were inoculated with porcine reproductive and respiratory syndrome virus (PRRSV; 5  10 5 TCID 50 of live PRRSV) or saline at gestational day 76. Gilts infected with PRRSV exhibited fever (p < 0.01) and reduced appetite (p < 0.001) for 2 weeks post- inoculation and were PRRSV-positive at parturition. Piglets born from infected and control gilts were weaned at postnatal day (PD) 1 and assigned to two groups. Group 1 was challenged with lipopolysac- charide (LPS, 5 lg/kg body weight i.p.) or saline on PD 14 and tissues were collected. Group 2 was tested in a T-maze task to assess spatial learning and in a 3-chamber arena with unfamiliar conspecifics to assess social behavior from PD 14–27. Microglia (CD11b + CD45 low ) isolated from Group 2 piglets at PD 28 were challenged ex vivo with LPS; a subset of cells was analyzed for MHCII expression. Maternal infec- tion did not affect offspring circulating TNFa, IL-10, or cortisol levels basally or 4 h post-LPS challenge. While performance in the T-maze task was not affected by maternal infection, both sociability and pref- erence for social novelty were decreased in piglets from infected gilts. There was no effect of maternal infection on microglial MHCII expression or LPS-induced cytokine production. Taken together, these results suggest the reduced social behavior elicited by maternal infection is not due to aberrant microglia activity postnatally. Ó 2016 Published by Elsevier Inc. 1. Introduction Maternal infection during pregnancy is associated with increased risk for development of neuropsychiatric disorders, such as autism and schizophrenia, in offspring (Atladóttir et al., 2010; Brown and Derkits, 2010). Studies in animal models suggest that during maternal immune activation (MIA), maternally-derived cytokines cross the placenta and affect fetal brain development (Gayle et al., 2004; Meyer et al., 2009b, 2007). Pregnant mice administered the viral mimetic polyinosinic:polycytidylic acid (poly I:C) at mid gestation give birth to offspring that display reduced social behavior, disruptions in vocalizations, and stereo- typic behavior (Malkova et al., 2012). Evidence of mediation by maternal cytokines comes from studies where pregnant dams were injected with recombinant IL-6 at E12.5, resulting in offspring with behavioral abnormalities similar to what is observed in viral infec- tion, poly I:C or LPS models (Smith et al., 2007). Furthermore, immunoneutralization of IL-6 in pregnant mice administered poly I:C at E12.5 normalized behavior of offspring (Smith et al., 2007). Other investigations revealed that direct injection of IL-17a into the fetal brain was sufficient to produce abnormal cortical develop- ment and autism-like phenotypes, while IL-6 was not. Additionally, ASD-like phenotypes produced either from maternal IL-6 or Poly I: C administration could be prevented by maternal pretreatment http://dx.doi.org/10.1016/j.bbi.2016.09.019 0889-1591/Ó 2016 Published by Elsevier Inc. ⇑ Corresponding author at: 227 Edward R. Madigan Laboratory, 1201 W. Gregory Drive, Urbana, IL 61801, USA. E-mail address: rwjohn@illinois.edu (R.W. Johnson). Brain, Behavior, and Immunity xxx (2016) xxx–xxx Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi Please cite this article in press as: Antonson, A.M., et al. Maternal viral infection during pregnancy elicits anti-social behavior in neonatal piglet offspring independent of postnatal microglial cell activation. Brain Behav. Immun. (2016), http://dx.doi.org/10.1016/j.bbi.2016.09.019