Please cite this article in press as: Foley, K.A., et al., Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysac- charide on social behavior in neonatal, adolescent, and adult rats: Implications for autism spectrum disorders. Int. J. Dev. Neurosci. (2014), http://dx.doi.org/10.1016/j.ijdevneu.2014.04.001 ARTICLE IN PRESS G Model DN-1867; No. of Pages 11 Int. J. Devl Neuroscience xxx (2014) xxx–xxx Contents lists available at ScienceDirect International Journal of Developmental Neuroscience j ourna l ho me page: www.elsevier.com/locate/ijdevneu Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: Implications for autism spectrum disorders Kelly A. Foley a,b,∗ , Derrick F. MacFabe b,d , Alisha Vaz b , Klaus-Peter Ossenkopp a,b,c , Martin Kavaliers a,b,c a Graduate Program in Neuroscience, The University of Western Ontario, London, ON N6A 5B7, Canada b Department of Psychology, The University of Western Ontario, London, ON N6A 5C2, Canada c The Kilee Patchell-Evans Autism Research Group, Department of Psychology, The University of Western Ontario, London, ON N6A 5C2, Canada d The Kilee Patchell-Evans Autism Research Group, Departments of Psychology and Psychiatry, Division of Developmental Disabilities, The University of Western Ontario, London, ON N6A 5C2, Canada a r t i c l e i n f o Article history: Received 11 January 2014 Received in revised form 7 April 2014 Accepted 7 April 2014 Keywords: Microbiota Short chain fatty acid Maternal immune activation Sex differences Neurodevelopmental disorders Social interaction a b s t r a c t Emerging evidence suggests that the gut microbiome plays an important role in immune functioning, behavioral regulation and neurodevelopment. Altered microbiome composition, including altered short chain fatty acids, and/or immune system dysfunction, may contribute to neurodevelopmental disorders such as autism spectrum disorders (ASD), with some children with ASD exhibiting both abnormal gut bacterial metabolite composition and immune system dysfunction. This study describes the effects of prenatal propionic acid (PPA), a short chain fatty acid and metabolic product of many antibiotic resistant enteric bacteria, and of prenatal lipopolysaccharide (LPS), a bacterial mimetic and microbiome compo- nent, on social behavior in male and female neonatal, adolescent and adult rats. Pregnant Long–Evans rats were injected once a day with either a low level of PPA (500 mg/kg SC) on gestation days G12–16, LPS (50 g/kg SC) on G12, or vehicle control on G12 or G12–16. Sex- and age-specific, subtle effects on behav- ior were observed. Both male and female PPA treated pups were impaired in a test of their nest seeking response, suggesting impairment in olfactory-mediated neonatal social recognition. As well, adolescent males, born to PPA treated dams, approached a novel object more than control animals and showed increased levels of locomotor activity compared to prenatal PPA females. Prenatal LPS produced subtle impairments in social behavior in adult male and female rats. These findings raise the possibility that brief prenatal exposure to elevated levels of microbiome products, such as PPA or LPS, can subtly influence neonatal, adolescent and adult social behavior. © 2014 ISDN. Published by Elsevier Ltd. All rights reserved. 1. Introduction Attention has increasingly focused on how host gut micro- bial populations, collectively known as the microbiome, influence health and disease. Through communication with the central and ∗ Corresponding author at: Department of Psychology, Graduate Program in Neu- roscience, Social Science Centre, Room 7418, The University of Western Ontario, 1151 Richmond St., London, ON N6A5C2, Canada. Tel.: +1 519 661 2111x81214; fax: +1 519 661 3961. E-mail addresses: kellyafoley@gmail.com (K.A. Foley), dmacfabe@uwo.ca (D.F. MacFabe), avaz3@uwo.ca (A. Vaz), ossenkop@uwo.ca (K.-P. Ossenkopp), kavalier@uwo.ca (M. Kavaliers). peripheral nervous system, modification in the various components of the microbiome have the potential to contribute to gastrointesti- nal (GI), immune, and neuropsychiatric disease (Cryan and Dinan, 2012; Nicholson et al., 2012; Stilling et al., 2014). Results of recent studies with germ-free mice have demonstrated that alterations in the GI microbiome are associated with changes in early gene expression, neurotransmitter turnover, stress response, immune function, as well as reduced social behavior (e.g., Desbonnet et al., 2013; Foster and Neufeld, 2013; Heijtz et al., 2011). Furthermore, alterations in the GI microbiome have been recently observed in a maternal immune activation (MIA) mouse model of autism spec- trum disorders (ASD) (Hsiao et al., 2013). There is mounting evidence that alterations in the composition of the microbiome and its metabolic products may contribute to http://dx.doi.org/10.1016/j.ijdevneu.2014.04.001 0736-5748/© 2014 ISDN. Published by Elsevier Ltd. All rights reserved.