Association of functional genetic variation in PP2A with prefrontal working memory processing.

Area of Science:

• Neuroscience
• Genetics
• Cognitive Science

Background:

• Dopamine D2 receptor signaling in the prefrontal cortex is crucial for working memory, particularly in schizophrenia.
• This signaling involves cAMP-dependent and independent pathways, with Protein-Phosphatase-2A (PP2A) being key in the latter.
• The PPP2R2B gene codes for a regulatory subunit of PP2A, linking it to D2 receptor function.

Purpose of the Study:

• To investigate if genetic variations in PPP2R2B, affecting its mRNA expression, are associated with prefrontal cortex function during working memory.
• To identify specific single nucleotide polymorphisms (SNPs) in PPP2R2B linked to gene expression and working memory performance.

Main Methods:

• Examined SNPs associated with PPP2R2B mRNA expression in two independent human postmortem prefrontal cortex samples.
• Tested replicated SNPs as predictors of prefrontal activity using functional magnetic resonance imaging (fMRI) during an N-Back working memory task in healthy individuals.

Main Results:

• A replicated SNP, rs959627, was found to predict prefrontal activity during the N-Back task.
• Individuals with the rs959627 T allele, associated with lower PPP2R2B expression, showed increased activity in the right inferior frontal gyrus (IFG).
• This heightened IFG activity correlated negatively with behavioral performance, suggesting reduced efficiency.

Conclusions:

• Genetic variation in PPP2R2B influences prefrontal cortex activity during working memory.
• The rs959627 SNP may indicate reduced right IFG efficiency in T-allele carriers, requiring greater neural activation for comparable task performance.