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Brain Advance Access published online on October 1, 2008
Brain, doi:10.1093/brain/awn248
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia

Alessandro Bertolino1,2, Leonardo Fazio1, Grazia Caforio1, Giuseppe Blasi1, Antonio Rampino1, Raffaella Romano1, Annabella Di Giorgio1, Paolo Taurisano1, Audrey Papp3, Julia Pinsonneault3, Danxin Wang3, Marcello Nardini1, Teresa Popolizio2 and Wolfgang Sadee3

1Group of Psychiatric Neuroscience, Department of Neurology and Psychiatry, University of Bari, Bari, 2Department of Neuroradiology, Istituto di Ricovero e Cura a Carattere Scientifico ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo (FG), Italy and 3Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, and Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, USA

Correspondence to: Alessandro Bertolino, MD, PhD, Dipartimento di Scienze Neurologiche e Psichiatriche, Università degli Studi di Bari, Piazza Giulio Cesare, 9 70124, Bari, Italy E-mail: a.bertolino{at}psichiat.uniba.it

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case–control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.

Key Words: dopamine; D2 receptor; working memory; prefrontal cortex; striatum

Abbreviations: BOLD, blood oxygenation level-dependent; D2L, D2 long; D2S, D2 short; PANSS, Positive and Negative Symptoms Scale; WM, working memory.

Received July 18, 2008. Revised August 18, 2008. Accepted September 8, 2008.


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