Early and adult hippocampal TGF-b1 overexpression have opposite effects on behavior Amaicha Mara Depino a,b,⇑ , Luciana Lucchina a , Fernando Pitossi c a Institute for Physiology, Molecular Biology and Neurosciences, CONICET-UBA, C1428EHA Buenos Aires, Argentina b Department of Physiology, Molecular and Cellular Biology, FCEyN, University of Buenos Aires, C1428EHA Buenos Aires, Argentina c Leloir Institute Foundation, Institute for Biochemical Investigations, CONICET, 1405 Buenos Aires, Argentina article info Article history: Received 2 February 2011 Received in revised form 29 April 2011 Accepted 16 May 2011 Available online 24 May 2011 Keywords: Transforming Growth Factor-beta 1 Autism Neuroinflammation Postnatal programming Mice Behavior abstract TGF-b1 is an anti-inflammatory cytokine that is augmented in the brain of autistic patients and that can affect brain development. In this work, we studied the effects of overexpressing TGF-b1 in the dentate gyrus of adult or young mice on behavior. TGF-b1 overexpression during postnatal development led to a long-term decrease in social interaction and to long-term increases in self-grooming and depression- related behaviors. Our analysis shows that these behavioral changes correlate with the long-term down- regulation of TGF-b1 and IL-6 expression in the dentate gyrus, as well as to decreases in the mRNA levels of the synaptic protein neuroligin 3 and in the number of Reelin-positive neurons in the dentate gyrus. In contrast, chronic expression of TGF-b1 during adulthood led to transient opposite effects on these behav- iors. These results show a central role of hippocampal TGF-b1 in the programming and modulation of social interaction, repetitive behavior and depression-related behavior. Finally, our data suggest a role of hippocampal TGF-b1 and early-life neuroinflammation in the development of the behavioral altera- tions observed in autism spectrum disorders. Ó 2011 Elsevier Inc. All rights reserved. 1. Introduction The Transforming Growth Factor-beta 1 (TGF-b1) is a cytokine that plays a role in the control of inflammatory and immune re- sponses (Kulkarni et al., 1993), but it can also worsen brain inflam- mation when it is overexpressed in the brain (Wyss-Coray et al., 1997). TGFbs and TGF-b receptors expression in the mouse brain is regulated during development (reviewed in Deverman and Patt- erson, 2009; Gomes et al., 2005) and it modulates cellular prolifer- ation and differentiation (Bottner et al., 2000). A role of TGF-b in the modulation of behavior has been suggested in clinical studies and tested in animal models. For example, the hippocampal TGF- b1 signaling pathway was reported as altered in autism (Vargas et al., 2005), schizophrenia and bipolar disorder (Benes et al., 2007), and manipulation of TGF-b signaling has been proposed as a possible treatment for anxiety and depression (Ageta et al., 2008; Dow et al., 2005; Zheng et al., 2009). In mice, hippocampal TGF-b1 modulates the response to spatial novelty and pre-pulse inhibition of the startle reflex (Sun et al., 2010). In rats, it was shown that decreased hippocampal TGF-b1 levels correlate with reduced neurogenesis and reduced response to novelty (Graciarena et al., 2010). The aim of this work was to further analyze the role of TGF-b1 in modulating behavior in the mouse. Among all the putative behaviors that could be altered by TGF-b1, we focused on behav- iors related to autism spectrum disorders (ASD) because this cyto- kine is particularly augmented in the ASD brain (Vargas et al., 2005) and its plasma levels reduced in patients (Ashwood et al., 2008). Therefore, we specifically focused on two murine behaviors linked to the major symptoms of ASD (American Psychiatric Asso- ciation, 2000): social interaction and self-grooming (Crawley, 2007). In addition, we evaluated anxiety- and depression-related behaviors because mood disorders and anxiety disorders show a high comorbidity with ASD (American Psychiatric Association, 2000; Hofvander et al., 2009). Different brain regions have been implicated in ASD, including the neocortex (Casanova and Trippe, 2009; Garbett et al., 2008; Vargas et al., 2005), the cerebellum (Pierce and Courchesne, 2001) and the dentate gyrus (DG) of the hippocampus (Greco et al., 2011; Lawrence et al., 2010; Saitoh et al., 2001; Wegiel et al., 2010). In situ hybridization analyses have shown that TGF-b recep- tor 1 is highly expressed in the DG during postnatal development but not in adulthood (Magdaleno et al., 2006). Others and we have shown that hippocampal TGF-b1 levels can be modulated by cen- tral and peripheral stimuli, both prenatally and in adulthood (Bat- tista et al., 2006; Cunningham et al., 2002; Graciarena et al., 2010). 0889-1591/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.bbi.2011.05.007 ⇑ Corresponding author. Address: Institute for Physiology, Molecular Biology and Neurosciences, CONICET-UBA, Int. Guiraldes S/N, Ciudad Universitaria, Pabellon 2, 2do piso, C1428EHA Buenos Aires, Argentina. Fax: +54 11 4576 3447. E-mail address: adepino@conicet.gov.ar (A.M. Depino). Brain, Behavior, and Immunity 25 (2011) 1582–1591 Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi