title: DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia.
abstract: The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.
authors.affiliation: Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University Aldo Moro, 70124 Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ursini
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Luisa
authors.initials: L
authors.lastname: Iacovelli
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sinibaldi
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism; D004843:Epistasis, Genetic; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008279:Magnetic Resonance Imaging; D000077152:Olanzapine; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D014150:Antipsychotic Agents; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D000242:Cyclic AMP; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000077152:Olanzapine