Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance

Abstract

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.

Figure 1. Association between DRD2 rs1076560 genotype and [¹²³I]IBZM binding.

Coronal section of the effect of DRD2 rs1076560 genotype (GG>GT) on [¹²³I]IBZM specific binding (V3″) in right putamen (left) and relative scatterplot of individual data points from the cluster differentiating the two groups (right).

Figure 2. Association between DRD2 rs1076560 genotype and [¹²³I]FP-CIT binding.

Coronal section of the effect of DRD2 rs1076560 genotype (GG>GT) on [¹²³I]FP-CIT specific binding (V3″) in left putamen (left) and relative scatterplot of individual data points from the cluster differentiating the two groups (right).

Figure 3. Correlation between BOLD fMRI activity in prefrontal cortex and the striatal dopamine D2 signaling factor in GG subjects.

3D rendering of the correlation between the striatal dopamine D2 signaling factor and BOLD fMRI activity during the 2-Back WM task in GG subjects (left) with the relative scatterplot of the correlation in prefrontal cortex showing individual data points (right).

Figure 4. Correlation between BOLD fMRI activity in prefrontal cortex and the striatal dopamine D2 signaling factor in GT subjects.

3D rendering of the correlation between the striatal dopamine D2 signaling factor and BOLD fMRI activity during the 2-Back WM task in GT subjects (left) with the relative scatterplot of the correlation in prefrontal cortex showing individual data points (right).