Altered expression and modulation of activity-regulated cytoskeletal associated protein (Arc) in serotonin transporter knockout rats Raffaella Molteni a , Francesca Calabrese a , Paola F. Maj a , Jocelien D.A. Olivier b , Giorgio Racagni a,c , Bart A. Ellenbroek d , Marco A. Riva a, ⁎ a Center of Neuropharmacology, Department of Pharmacological Sciences, Universita’ di Milano, Via Balzaretti 9, 20133 Milan, Italy b Department of Cognitive Neurosciences, University of Nijmegen, The Netherlands c I.R.C.C.S. San Giovanni di Dio-Fatebenefratelli, Brescia, Italy d Department of Neuropharmacology, Evotec GmbH, Hamburg, Germany Received 11 February 2009; received in revised form 5 May 2009; accepted 9 June 2009 KEYWORDS Depression; Serotonin transporter; Stress; Arc; Gene expression Abstract A gene variant in the human serotonin transporter (SERT) can increase the vulnerability to mood disorders. SERT knockout animals show similarities to the human condition and represent an important tool to investigate the mechanisms underlying the pathologic condition in humans. Along this line of thinking, we used SERT KO rats (SERT +/- and SERT -/- ) to investigate abnormalities in the expression and function of the activity-regulated gene Arc (Activity- regulated cytoskeletal associated protein) and the early inducible gene Zif-268, (zinc finger binding protein clone 268), which are important players in neuronal plasticity. We found lower basal Arc mRNA levels in hippocampus and prefrontal cortex of mutant rats in comparison with wild-type animals. Moreover SERT mutant rats show altered stress responsiveness. Indeed an acute swim stress significantly up-regulated the levels of Arc mRNA in hippocampus and prefrontal cortex, as well as of Zif-268 in frontal cortex, only in SERT +/- and SERT -/- rats. These alterations may be associated to behavioral traits linked to SERT and may contribute to the neuroplastic and morphological changes observed in depression. © 2009 Elsevier B.V. and ECNP. All rights reserved. 1. Introduction Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including depression and schizophrenia. Indeed the modulation of serotonin biosynthesis and the regulation of its synaptic availability are the primary mechanisms through which antidepressant drugs work. In line with this possibility, major vulnerability genes for mood disorders are related to the serotonergic system, including the biosynthetic enzyme tryptophane hydroxylase (TPH), the serotonin transporter (SERT or ⁎ Corresponding author. Tel.: +39 02 50318334; fax: +39 02 50318278. E-mail address: M.Riva@unimi.it (M.A. Riva). 0924-977X/$ - see front matter © 2009 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2009.06.008 www.elsevier.com/locate/euroneuro European Neuropsychopharmacology (2009) 19, 898—904