Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition

Andreas Meyer-Lindenberg, Richard E. Straub, Barbara K. Lipska, Beth A. Verchinski, Terry Goldberg, Joseph H. Callicott, Michael F. Egan, Stephen S. Huffaker, Venkata S. Mattay, Bhaskar Kolachana, Joel E. Kleinman, Daniel R. Weinberger

Research output: Contribution to journalArticle

Abstract

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia.

Original languageEnglish (US)
Pages (from-to)672-682
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Meyer-Lindenberg, A., Straub, R. E., Lipska, B. K., Verchinski, B. A., Goldberg, T., Callicott, J. H., Egan, M. F., Huffaker, S. S., Mattay, V. S., Kolachana, B., Kleinman, J. E., & Weinberger, D. R. (2007). Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. Journal of Clinical Investigation, 117(3), 672-682. https://doi.org/10.1172/JCI30413