title: Association of functional genetic variation in PP2A with prefrontal working memory processing.
abstract: 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.
authors: Department of Basic Medical Science, Neuroscience, and Sense Organs - University of Bari 'Aldo Moro', Piazza Giulio Cesare 11, 70124 Bari, Italy; Psychiatry Unit - Bari University Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors: Antonio
authors: A
authors: Rampino
authors: Department of Basic Medical Science, Neuroscience, and Sense Organs - University of Bari 'Aldo Moro', Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors: Pasquale
authors: P
authors: Di Carlo
authors: Department of Basic Medical Science, Neuroscience, and Sense Organs - University of Bari 'Aldo Moro', Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors: Leonardo
authors: L
authors: Fazio
authors: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, 21205, Baltimore (MD), USA.
authors: Gianluca
authors: G
authors: Ursini
authors: Department of Basic Medical Science, Neuroscience, and Sense Organs - University of Bari 'Aldo Moro', Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors: Giulio
authors: G
authors: Pergola
authors: Department of Bioscience, Biotechnologies and Biopharmaceutics - - University of Bari 'Aldo Moro', Via E. Orabona, 4, 70124 Bari, Italy.
authors: Caterina
authors: C
authors: De Virgilio
authors: Department of Bioscience, Biotechnologies and Biopharmaceutics - - University of Bari 'Aldo Moro', Via E. Orabona, 4, 70124 Bari, Italy.
authors: Gemma
authors: G
authors: Gadaleta
authors: University of Naples SUN, Department of Psychiatry, Largo Madonna delle Grazie 1, 80138 Naples, Italy.
authors: Giulia Maria
authors: GM
authors: Giordano
authors: Department of Basic Medical Science, Neuroscience, and Sense Organs - University of Bari 'Aldo Moro', Piazza Giulio Cesare 11, 70124 Bari, Italy; Psychiatry Unit - Bari University Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors: Alessandro
authors: A
authors: Bertolino
authors: Psychiatry Unit - Bari University Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy. Electronic address: blasi.seppe@gmail.com.
authors: Giuseppe
authors: G
authors: Blasi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D054648:Protein Phosphatase 2; D010100:Oxygen
keywords: D2 dopamine receptor; Prefrontal cortex; Protein phosphatase 2A; Working memory; fMRI