Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.
BACKGROUND
Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.


METHODS
Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory.


RESULTS
Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.


CONCLUSIONS
Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.
Bertolino
Alessandro
A
Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy. a.bertolino@psichiat.uniba.it
Taurisano
Paolo
P
Pisciotta
Nicola Marco
NM
Blasi
Giuseppe
G
Fazio
Leonardo
L
Romano
Raffaella
R
Gelao
Barbara
B
Lo Bianco
Luciana
L
Lozupone
Madia
M
Di Giorgio
Annabella
A
Caforio
Grazia
G
Sambataro
Fabio
F
Niccoli-Asabella
Artor
A
Papp
Audrey
A
Ursini
Gianluca
G
Sinibaldi
Lorenzo
L
Popolizio
Teresa
T
Sadee
Wolfgang
W
Rubini
Giuseppe
G
D000328:Adult; D000704:Analysis of Variance; D001549:Benzamides / Q000378:metabolism; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology; D011759:Pyrrolidines / Q000378:metabolism; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D001549:Benzamides; D018492:Dopamine Antagonists; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide