Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring Fabien Boulle a,b,1 , Jodi L. Pawluski a,c, ⁎ ,1 , Judith R. Homberg d , Barbie Machiels a , Yvet Kroeze d , Neha Kumar a , Harry W.M. Steinbusch a , Gunter Kenis a , Daniel L.A. van den Hove a,e a School for Mental Health and Neuroscience (MHeNS), Maastricht University, European Graduate School of Neuroscience (EURON), Universiteitssingel 50, P.O. box 616, 6200, MD, Maastricht, The Netherlands b Center for Psychiatry and Neuroscience, INSERM, U894, University Pierre and Marie Curie, Paris, France c University of Liege, GIGA-Neurosciences, 1 avenue de l'Hôpital (Bat. B36), B-4000 Liège, Belgium d Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University Medical Centre, Department of Cognitive Neuroscience, Geert Grooteplein 21, 6525 EZ Nijmegen, The Netherlands e Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080 Wuerzburg, Germany abstract article info Article history: Received 21 July 2015 Revised 16 December 2015 Accepted 29 January 2016 Available online 1 February 2016 A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how develop- mental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocam- pal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague–Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress + Vehicle, 2) No Stress + Fluoxetine, 3) Prenatal Stress + Vehicle, and 4) Prenatal Stress + Fluoxetine. Primary results show that, in adult female offspring, devel- opmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri- methylated mark at the corresponding promoter. There was also a significant negative correlation between hip- pocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or de- velopmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect–related behaviors and their underlying molecular mechanisms. © 2016 Elsevier Inc. All rights reserved. Keywords: SSRI Prenatal stress Neuroplasticity Hippocampus Postpartum depression Serotonin Epigenetic Maternal behavior Sex differences Gender Introduction Selective serotonin reuptake inhibitor (SSRI) medications are com- monly used for the treatment of mood disorders during pregnancy, with up to 10% of pregnant women being prescribed these medications (Cooper et al., 2007; Fleschler and Peskin, 2008; Leung and Kaplan, 2009; Oberlander et al., 2006). SSRIs cross the placental barrier and are present in breast milk; consequently playing a role in fetal and child development (Homberg et al., 2010; Kristensen et al., 1999; Rampono et al., 2004). Chronic SSRI treatment often has few negative effects on the mother, however, recent research suggests long-term ef- fects of pre- and/or-postnatal exposure to SSRIs on neurodevelopment of offspring (Ansorge et al., 2004; Gemmel et al., 2015; Homberg et al., 2010; Pawluski, 2012; Pawluski et al., 2012b; Rayen et al., 2011, 2013, 2014, 2015). Given that serotonin (5-HT) plays a significant role in brain develop- ment, modulating processes such as cell division, differentiation, migra- tion, and synaptogenesis (Azmitia, 2001; Lipton and Kater, 1989), it is not surprising that early exposure to SSRI medications may have a long-term effect on neurodevelopment. Recent clinical studies report Hormones and Behavior 80 (2016) 47–57 ⁎ Corresponding author at: IRSET-INSERM U1085, University of Rennes 1, Campus Beaulieu Bat 13, Room 135/2, 35042 Rennes Cedex, France. E-mail addresses: j.pawluski@gmail.com, jodi.pawluski@univ-rennes1.fr (J.L. Pawluski). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.yhbeh.2016.01.017 0018-506X/© 2016 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Hormones and Behavior journal homepage: www.elsevier.com/locate/yhbeh