DARPP-32 transcripts are upregulated in the prefrontal cortex of major psychiatric disorders and associated with genetic variants

  • Y. K
  • T.M. H
  • T. Y
  • et al.
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Abstract

Background: Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been implicated in the pathogenesis of schizophrenia and bipolar disorderbecause of itsrole as a molecular integrator ofdopaminergic and glutaminergic signaling.Previously reported resquencing of DARPP-32 identified a frequent haplotype associated with the expression of DARPP-32 in the dorsolateral prefrontal cortex, cognition and frontostriatal function using imaging in normal controls (Meyer-Lindenberg et al., 2007). In this study, we investigated the expression of two major DARPP-32 transcripts, full-length and truncated, in the dorsolateral prefrontal cortex (DLPFC) in a large cohort of patients with schizophrenia, bipolar disorder and major depression as well as controls across the lifespan. We also analyzed associations of expression of these transcripts with genetic variants of DARPP-32. Methods: We examined the expression of DARPP-32 transcripts in the postmortem DLPFC of 324 normal controls, including 42 fetal samples, 176patients with schizophrenia, 61patients with bipolar disorder and 138 subjects with major depression disorder by quantitative real-time polymerase chainreactionmethodsusing Taqman ABI assays. We examinedassociations withgenetic variation in DARPP-32 for 58 SNPs genotyped using 1M Illumina BeadArrays. We used ANCOVAs with post-hoc Bonferroni corrections to analyze the data. Results: Developmental expression patterns of full length DARPP- 32 (FL-DARPP-32) and the splice variantencoding truncated- DARPP-32protein (t-DARPP-32)differed markedly. Expression of FL-DARPP-32 was high during the prenatal period, dropped at birth, and then increased gradually throughout the postnatal life until old age. In contrast, t-DARPP-32 was expressed at very low levels prenatally, increased sharply from birth to pubescent ages and remained relatively stable throughout the rest of life. There were dramatic differences in the expression of both transcripts between the diagnostic groups. FL-DARPP-32 was significantly increased in major depression as compared to all other groups (p=7.3x10-4). The expression of t-DARPP-32 as well as the ratio of t-DARPP-32 to FLDARPP32 were increased in schizophrenia (p=3.4x10-7) and bipolar disorder (p<1.0x10-17) as compared with normal controls. Expression of t-DARPP-32 in bipolar disorder patients was also significantly higher than in patients with schizophrenia (p=3.3x10-12) and patients with major depression (p<1.0x1017). We did not detect the effects of nicotine, antipsychotic medication, antidepressants or lithium on the expression levels of the two transcripts. We analysed 58 SNPs in the DARPP-32 regionand found that 4 SNPs predicted expression of t-DARPP-32, including2 SNPs(rs90974 and rs3764352)that were previously associated with schizophrenia, cognitive and imaging phenotypes (p<0.001). Discussion: Our data show that the expression levels of FLDARPP- 32 and t-DARPP-32are altered in patients with schizophrenia and affective disorders.Although preliminary analysis did not find the effects of medication on the expression of DARPP- 32 splice variants, it cannot be precluded that the differences between diagnostic groups are due to psychotropic drugs. The increased ratio of truncated/full length DARPP-32 may lead to an attenuation of dopamine signaling in the DLPFC because t-DARPP-32 lacks the Threonine 34 phosphorylation site and proteinphosphatase inhibitory domain, which are critical for dopamine signaling in thebrain.In addition, t-DARPP-32may interfere with PKA inhibitionby FL-DARPP-32via adominant negative mechanismand then activate phosphoinositide 3-Kinase/ Akt pathway signaling (Guet al. 2009).Therefore, the data suggest that this pathway may contribute to the pathophysiology of schizophrenia and affective disorders. Moreover, we foundthat2 SNPs, rs907094 and rs3764352, which were associated with schizophrenia,performance on several cognitive tests and frontostriatal functions, predicted expression of t-DARPP-32. Our results suggest that variation in PPP1R1B affects splicing of DARPP-32 and identify potential molecular mechanisms of the pathogenesis of mental disorders.

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Y., K., T.M., H., T., Y., C., L., D.R., W., J.E., K., & B.K., L. (2011). DARPP-32 transcripts are upregulated in the prefrontal cortex of major psychiatric disorders and associated with genetic variants. Neuropsychopharmacology. Y. Kunii, National Institute of Mental Health, Bethesda, United States: Nature Publishing Group. Retrieved from http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed10&NEWS=N&AN=70607491

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