Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans.
Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D(2) receptors (encoded by DRD(2)) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D(2) proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD(2) polymorphism (rs1076560) causing reduced presynaptic D(2) 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 DRD(2)/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 DRD(2) 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 D(2) knock-out animals (D2R(-/-)) indicate that DAT and D(2) proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD(2) and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.
Bertolino
Alessandro
A
Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, 70124 Bari, Italy. a.bertolino@psichiat.uniba.it
Fazio
Leonardo
L
Di Giorgio
Annabella
A
Blasi
Giuseppe
G
Romano
Raffaella
R
Taurisano
Paolo
P
Caforio
Grazia
G
Sinibaldi
Lorenzo
L
Ursini
Gianluca
G
Popolizio
Teresa
T
Tirotta
Emanuele
E
Papp
Audrey
A
Dallapiccola
Bruno
B
Borrelli
Emiliana
E
Sadee
Wolfgang
W
D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D001931:Brain Mapping; D003342:Corpus Striatum / Q000098:blood supply / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D007839:Functional Laterality; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018598:Minisatellite Repeats / Q000235:genetics; D009434:Neural Pathways / Q000098:blood supply / Q000502:physiology; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000098:blood supply / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D012044:Regression Analysis; D055815:Young Adult
D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D010100:Oxygen