Variation in prefrontal dopaminergic signaling mediated by D2 receptor has been implicated in cognitive phenotypes of schizophrenia, including working memory. Molecular cascades downstream of D2 receptor include a cAMP-dependent- and a cAMP-independent-pathway. Protein-Phosphatase-2A (PP2A) is a key partner of D2 receptor in cAMP-independent signaling. This enzyme comprises a regulatory subunit that is coded by PPP2R2B gene. Given the molecular relationship between PP2A and D2 signaling, we hypothesized genetic variation in PPP2R2B affecting mRNA expression of this gene in prefrontal cortex to be associated with prefrontal processing during working memory. In order to probe such a hypothesis we investigated SNPs associated with PPP2R2B expression in two independent samples of human postmortem prefrontal cortex. Then, we tested SNPs for which association was replicated as predictors of prefrontal activity during WM as probed by functional magnetic resonance (fMRI) in a sample of healthy humans. We found that a SNP associated with PPP2R2B expression (rs959627) predicted prefrontal activity during the N-Back working memory task. In particular, individuals carrying rs959627T allele, a condition associated with lower PPP2R2B expression in postmortem prefrontal cortex, showed greater activity in right inferior frontal gyrus (IFG) during N-Back compared to CC subjects. Furthermore, such an activity was negatively correlated with behavioral performance at the task. Consistently with previous studies, these findings suggest reduced right IFG efficiency during working memory processing in rs959627 T-carriers, as indexed by their greater need to activate this brain region in order to achieve similar levels of behavioral proficiency as compared to CC individuals.
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