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Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression

Molecular Psychiatry volume 19, pages 192–199 (2014)Cite this article

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Abstract

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been of interest in schizophrenia owing to its critical function in integrating dopaminergic and glutaminergic signaling. In a previous study, we identified single-nucleotide polymorphisms (SNPs) and a frequent haplotype associated with cognitive and imaging phenotypes that have been linked with schizophrenia, as well as with expression of prefrontal cortical DARPP-32 messenger RNA (mRNA) in a relatively small sample of postmortem brains. In this study, we examined the association of expression of two major DARPP-32 transcripts, full-length (FL-DARPP-32) and truncated (t-DARPP-32), with genetic variants of DARPP-32 in three brain regions receiving dopaminergic input and implicated in schizophrenia (the dorsolateral prefrontal cortex (DLPFC), hippocampus and caudate) in a much larger set of postmortem samples from patients with schizophrenia, bipolar disorder, major depression and normal controls (>700 subjects). We found that the expression of t-DARPP-32 was increased in the DLPFC of patients with schizophrenia and bipolar disorder, and was strongly associated with genotypes at SNPs (rs879606, rs90974 and rs3764352), as well as the previously identified 7-SNP haplotype related to cognitive functioning. The genetic variants that predicted worse cognitive performance were associated with higher t-DARPP-32 expression. Our results suggest that variation in PPP1R1B affects the abundance of the splice variant t-DARPP-32 mRNA and may reflect potential molecular mechanisms implicated in schizophrenia and affective disorders.

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Acknowledgements

We thank Liqin Wang and Vesna Imamovic for their technical expertise, Amy Deep-Soboslay and Dr Llewellyn Bigelow for their diagnostic contributions, Dr Mary Herman for her contribution to the Clinical Brain Disorders Branch/National Institute of Mental Health brain collection, and Dr Ronald Zielke, Robert Johnson and Robert Vigorito at the NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland School of Medicine, for their collection of brains. We thank Dr Andreas Meyer-Lindenberg for his valuable comments on the paper. We also thank the families of the deceased for the donations of brain tissue, and their time and effort devoted to the consent process and interviews. This research was supported by the Intramural Research Program of the National Institute of Mental Health funding of the Weinberger and Kleinman laboratories.

Author contributions

YK, BKL, DRW and JEK designed the research and contributed to interpretations of all experiments and to editing of the manuscript; YK, BKL, CL, BK and DD performed the research; YK, BKL, TY and DD analyzed the data; and YK, BKL, DRW and JEK wrote the paper.

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Authors and Affiliations

  1. Division of Intramural Research Programs, Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA

    Y Kunii, T M Hyde, T Ye, C Li, B Kolachana, D Dickinson, D R Weinberger, J E Kleinman & B K Lipska

  2. Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan

    Y Kunii

  3. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    T M Hyde, T Ye & D R Weinberger

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  1. Y Kunii
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Correspondence to B K Lipska.

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Kunii, Y., Hyde, T., Ye, T. et al. Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression. Mol Psychiatry 19, 192–199 (2014). https://doi.org/10.1038/mp.2012.174

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