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The Journal of Neuroscience, April 12, 2006, 26(15):3918-3922; doi:10.1523/JNEUROSCI.4975-05.2006

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Brief Communications
Additive Effects of Genetic Variation in Dopamine Regulating Genes on Working Memory Cortical Activity in Human Brain

Alessandro Bertolino,^1,3,4 Giuseppe Blasi,^1,3 Valeria Latorre,¹ Valeria Rubino,¹ Antonio Rampino,¹ Lorenzo Sinibaldi,^2,6 Grazia Caforio,¹ Vittoria Petruzzella,² Antonio Pizzuti,^5,6 Tommaso Scarabino,⁴ Marcello Nardini,¹ Daniel R. Weinberger,³ and Bruno Dallapiccola^5,6

¹Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Neurological and Psychiatric Sciences, and ²Department of Medical Biochemistry and Medical Biology, University of Bari, 70124 Bari, Italy, ³Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, ⁴Department of Neuroradiology, Istituto di Ricovero e Cura e Carrattere Scientifico "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo (Foggia), Italy, ⁵IRCCS-CSS Mendel, 00198 Rome, Italy, and ⁶Department of Experimental Medicine and Pathology, University La Sapienza, 00100 Rome, Italy

Correspondence should be addressed to Dr. Alessandro Bertolino, Dipartimento di Scienze Neurologiche e Psichiatriche, Universita’ degli Studi di Bari, Piazza Giulio Cesare, 9, 70124 Bari, Italy. Email: bertolia{at}psichiat.uniba.it

Functional polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) genes modulate dopamine inactivation, which is crucial for determining neuronal signal-to-noise ratios in prefrontal cortex during working memory. We show that the COMT Met¹⁵⁸ allele and the DAT 3' variable number of tandem repeat 10-repeat allele are independently associated in healthy humans with more focused neuronal activity (as measured with blood oxygen level-dependent functional magnetic resonance imaging) in the working memory cortical network, including the prefrontal cortex. Moreover, subjects homozygous for the COMT Met allele and the DAT 10-repeat allele have the most focused response, whereas the COMT Val and the DAT 9-repeat alleles have the least. These results demonstrate additive genetic effects of genes regulating dopamine signaling on specific neuronal networks subserving working memory.

Key words: dorsolateral prefrontal cortex; anterior cingulate; working memory; dopamine; catechol-O-methyltransferase; dopamine transporter

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Received Nov. 22, 2005; revised Jan. 30, 2006; accepted Feb. 27, 2006.

Correspondence should be addressed to Dr. Alessandro Bertolino, Dipartimento di Scienze Neurologiche e Psichiatriche, Universita’ degli Studi di Bari, Piazza Giulio Cesare, 9, 70124 Bari, Italy. Email: bertolia{at}psichiat.uniba.it

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