title: Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression.
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.
authors.affiliation: 1] Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA [2] Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kunii
authors.affiliation: 1] Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA [2] Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: 1] Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA [2] Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ye
authors.affiliation: Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kolachana
authors.affiliation: Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Dickinson
authors.affiliation: 1] Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA [2] Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Section on Neuropathology, Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Lipska
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005333:Fetus; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497928:PPP1R1B protein, human