Transcriptomic context of <i>DRD1</i> is associated with prefrontal activity and behavior during working memory

Abstract

Dopamine D₁ receptor (D₁R) signaling shapes prefrontal cortex (PFC) activity during working memory (WM). Previous reports found higher WM performance associated with alleles linked to greater expression of the gene coding for D₁Rs (<i>DRD1</i>). However, there is no evidence on the relationship between genetic modulation of <i>DRD1</i> expression in PFC and patterns of prefrontal activity during WM. Furthermore, previous studies have not considered that D₁Rs are part of a coregulated molecular environment, which may contribute to D₁R-related prefrontal WM processing. Thus, we hypothesized a reciprocal link between a coregulated (i.e., coexpressed) molecular network including <i>DRD1</i> and PFC activity. To explore this relationship, we used three independent postmortem prefrontal mRNA datasets (total <i>n</i> = 404) to characterize a coexpression network including <i>DRD1</i> Then, we indexed network coexpression using a measure (polygenic coexpression index-<i>DRD1</i>-PCI) combining the effect of single nucleotide polymorphisms (SNPs) on coexpression. Finally, we associated the <i>DRD1</i>-PCI with WM performance and related brain activity in independent samples of healthy participants (total <i>n</i> = 371). We identified and replicated a coexpression network including <i>DRD1</i>, whose coexpression was correlated with <i>DRD1</i>-PCI. We also found that <i>DRD1</i>-PCI was associated with lower PFC activity and higher WM performance. Behavioral and imaging results were replicated in independent samples. These findings suggest that genetically predicted expression of <i>DRD1</i> and of its coexpression partners stratifies healthy individuals in terms of WM performance and related prefrontal activity. They also highlight genes and SNPs potentially relevant to pharmacological trials aimed to test cognitive enhancers modulating <i>DRD1</i> signaling.