Research Report Decreased reuptake of dopamine in the dorsal striatum in the absence of alpha-synuclein Heramb Chadchankar a, ⁎ , Jouni Ihalainen b , Heikki Tanila b, c , Leonid Yavich a a School of Pharmacy, Faculty of Health Sciences, P. O. Box 1627, University of Eastern Finland, Kuopio Campus, Kuopio 70211, Finland b A. I. Virtanen Institute for Molecular Sciences, P. O. Box 1627, University of Eastern Finland, Kuopio 70211, Finland c Department of Neurology, Kuopio University Hospital, University of Eastern Finland, Kuopio 70211, Finland ARTICLE INFO ABSTRACT Article history: Accepted 19 January 2011 Available online 26 January 2011 The presynaptic protein alpha-synuclein (α-syn) plays a role in dopaminergic neuro- transmission in the nigrostriatal dopaminergic system. Mutations in this protein have been linked to pathogenesis of Parkinson's disease. However, the details of regulation of dopamine homeostasis by α-syn and its molecular targets are generally unknown. We investigated the effect of α-syn deletion on striatal dopaminergic homeostasis. Two α-syn deficient mouse lines, one carrying a spontaneous deletion of α-syn locus and the other a transgenic α-syn knockout, were used in the study. Stimulated and basal extracellular dopamine levels were determined in the dorsal striatum by in vivo voltammetry and in vivo microdialysis, respectively. Dopamine transporter expression was studied by immunohis- tochemistry. Stimulated dopamine overflow and basal extracellular dopamine levels were higher in mice lacking α-syn with a concomitant decrease in dopamine transporter expression and reuptake in the dorsal striatum. We show that α-syn deletion produces significant adaptive changes in the striatal dopaminergic system via modulation of reuptake. © 2011 Elsevier B.V. All rights reserved. Keywords: Dopamine Alpha-synuclein Dopamine transporter Reuptake in vivo voltammetry in vivo microdialysis 1. Introduction Mutations in alpha-synuclein (α-syn) have been linked to certain forms of familial Parkinson's disease (PD) and other neurodegenerative disorders (Spillantini et al., 1997; Lee and Trojanowski, 2006). α-syn plays a role in dopamine synthesis (Perez et al., 2002), alters the compartmentalization of dopa- mine storage pool (Cabin et al., 2000) and neurotransmitter release (Abeliovich et al., 2000). α-syn appears to have a minor effect on DA release at short, relatively weak stimuli but plays an important role in recycling of dopamine storage pool at intense (Yavich et al., 2004; Nemani et al., 2010) or during repetitive stimuli (Abeliovich et al., 2000; Yavich et al., 2004). Neurotransmission during burst stimulation, which mimics repetitive firing of dopamine neurons, is sustained by effective reuptake (Stevens and Wesseling, 1999). Efficient reuptake replenishes the readily releasable pool (RRP), which is the primary source of presynaptic dopamine available for release during bursting. Several in vitro studies have shown that α-syn plays a role in the trafficking of the dopamine transporter (DAT) (Lee et al., 2001; Wersinger and Sidhu, 2003). However, modulation of reuptake in α-syn knockout mice has not been revealed at least in ex vivo experiments in slices (Abeliovich et al., 2000; Senior et al., 2008). BRAIN RESEARCH 1382 (2011) 37 – 44 ⁎ Corresponding author. Fax: +358 17 162 424. E-mail address: heramb.chadchankar@uef.fi (H. Chadchankar). 0006-8993/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2011.01.064 available at www.sciencedirect.com www.elsevier.com/locate/brainres