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

• Published in: Molecular psychiatry Vol. 19; no. 2; pp. 192 - 199
• Main Authors: Kunii, Y, Hyde, T M, Ye, T, Li, C, Kolachana, B, Dickinson, D, Weinberger, D R, Kleinman, J E, Lipska, B K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2014; Nature Publishing Group
• Subjects: 631/208/2489/144; 692/699/476; Adolescent; Adult; Adult and adolescent clinical studies; Affective disorders; Aged; Aged, 80 and over; Alternative splicing; Animals; Antipsychotic Agents - pharmacology; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Bipolar disorders; Brain - drug effects; Brain - growth & development; Brain - metabolism; Brain research; Child; Child, Preschool; Cognition & reasoning; Cognitive ability; DARPP-32 protein; Depressive Disorder, Major - genetics; Depressive Disorder, Major - metabolism; Dopamine; Dopamine and cAMP-Regulated Phosphoprotein 32 - genetics; Dopamine and cAMP-Regulated Phosphoprotein 32 - metabolism; Dopamine receptors; Female; Fetus; Gene expression; Genes; Genetic aspects; Genetic diversity; Genetic research; Haplotypes; Humans; Infant; Kinases; Male; Medical sciences; Medicine; Medicine & Public Health; Mental disorders; Mental health; Middle Aged; Miscellaneous; Molecular modelling; Molecular weight; Mood disorders; Neuroimaging; Neurosciences; original-article; Pharmacotherapy; Phenotypes; Phosphatase; Phosphorylation; Physiology; Prefrontal cortex; Proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Psychosis; Rats; Rats, Sprague-Dawley; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - genetics; Schizophrenia - metabolism; Single-nucleotide polymorphism; United States > US; DARPP-32; postmortem brain; truncated; bipolar disorder; schizophrenia; dopamine; Mood disorder; Human; Dopamine; Central nervous system; Postmortem; Schizophrenia; Bipolar disorder; Catecholamine; Encephalon; Psychosis; Neurotransmitter; Genetics
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2012.174

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.