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The Journal of Neuroscience, January 28, 2009, 29(4):1224-1234; doi:10.1523/JNEUROSCI.4858-08.2009
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Behavioral/Systems/Cognitive
Genetically Determined Interaction between the Dopamine Transporter and the D2 Receptor on Prefronto-Striatal Activity and Volume in Humans
Alessandro Bertolino,1 Leonardo Fazio,1 Annabella Di Giorgio,1 Giuseppe Blasi,1 Raffaella Romano,1 Paolo Taurisano,1 Grazia Caforio,1 Lorenzo Sinibaldi,2,3 Gianluca Ursini,1,2 Teresa Popolizio,4 Emanuele Tirotta,5 Audrey Papp,6 Bruno Dallapiccola,2,3,4 Emiliana Borrelli,5 andWolfgang Sadee6 1Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, 70124 Bari, Italy, 2Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Casa Sollievo della Sofferenza (CSS)–Mendel Institute, 00198 Rome, Italy, 3Department of Experimental Medicine, Sapienza University, 00100 Rome, Italy, 4Department of Neuroradiology, IRCCS CSS, 71013 San Giovanni Rotondo, Foggia, Italy, 5Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California 92697, and 6Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, and Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, Ohio 43210
Correspondence should be addressed to Dr. Alessandro Bertolino, Dipartimento di Scienze Neurologiche e Psichiatriche, Università degli Studi di Bari, Piazza Giulio Cesare 9, 70124 Bari, Italy. Email: a.bertolino{at}psichiat.uniba.it
Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D2 receptors (encoded by DRD2) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D2 proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD2 polymorphism (rs1076560) causing reduced presynaptic D2 receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD2/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD2 allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D2 knock-out animals (D2R–/–) indicate that DAT and D2 proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD2 and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.
Key words: working memory; recognition memory; fMRI; dopamine; transport; D2; receptor
Received Oct. 8, 2008; revised Nov. 14, 2008; accepted Dec. 20, 2008.
Correspondence should be addressed to Dr. Alessandro Bertolino, Dipartimento di Scienze Neurologiche e Psichiatriche, Università degli Studi di Bari, Piazza Giulio Cesare 9, 70124 Bari, Italy. Email: a.bertolino{at}psichiat.uniba.it
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