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. 2014 May 12;9(5):e95997.
doi: 10.1371/journal.pone.0095997. eCollection 2014.

DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory

Annabella Di Giorgio  1 , Ryan M Smith  2 , Leonardo Fazio  3 , Enrico D'Ambrosio  3 , Barbara Gelao  3 , Aldo Tomasicchio  3 , Pierluigi Selvaggi  3 , Paolo Taurisano  3 , Tiziana Quarto  4 , Rita Masellis  3 , Antonio Rampino  3 , Grazia Caforio  3 , Teresa Popolizio  1 , Giuseppe Blasi  3 , Wolfgang Sadee  2 , Alessandro Bertolino  5
Affiliations

DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory

Annabella Di Giorgio et al. PLoS One. .

Abstract

Background: Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume.

Methods: A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI.

Results: We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups.

Conclusions: The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Interaction between Working Memory behavioral performance, DRD2 rs1076560 and CHNRA5 rs16969968 genotypes.
Mean ± Standard Errors correct responses (DRD2-GG, left panel; DRD2-Tcarriers, right panel) showing the interaction between the two genotypes. See text for statistics.
Figure 2
Figure 2. Interaction between DRD2 rs1076560 and CHNRA5 rs16969968 on prefrontal physiology at 2-Back.
3Dimensional rendering (left, image thresholded at p<0.005, uncorrected) and mean ±0.95 CIs of BOLD response (right) of the interaction between DRD2 rs1076560 and CHNRA5 rs16969968 on working memory DLPFC activity.
Figure 3
Figure 3. Correlation between BOLD fMRI in prefrontal cortex and Working Memory accuracy in CHRNA5-GA/DRD2-GT subjects.
3Dimensional rendering (left, image thresholded at p<0.005, uncorrected) of the correlation between BOLD response in DLPFC and percentage of correct responses at 2-Back task in CHRNA5-GA/DRD2-GT subjects. On the right, relative scatterplot is shown indicating individual data points.
Figure 4
Figure 4. Interaction between DRD2 rs1076560 and CHNRA5 rs16969968 on prefrontal gray matter volume.
3Dimensional rendering (left, image thresholded at p<0.005, uncorrected) and mean ±0.95 CIs of gray matter content (right) of the interaction between DRD2 rs1076560 and CHNRA5 rs16969968 on DLPFC gray matter.
See this image and copyright information in PMC

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