Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University Aldo Moro, 70124 Bari, Italy.
Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1158-63. doi: 10.1073/pnas.1013535108. Epub 2010 Dec 27.
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.
D2/AKT1/GSK-3β 信号通路参与了多巴胺的下游细胞内效应，与精神分裂症认知缺陷和相关大脑活动的病理生理学有关，也与抗精神病药物治疗的反应有关。D2（DRD2 rs1076560）和 AKT1（AKT1 rs1130233）基因的多态性与各自的蛋白质表达以及包括注意力在内的高级认知和大脑功能有关。鉴于它们之间的关系很强，我们研究了这些多态性对与该信号通路相关的多种分子和体内表型的相互作用。我们测量了人类外周血单核细胞中的 AKT1 和 GSK-3β 蛋白及其磷酸化水平、注意力控制过程中扣带回响应的功能磁共振成像、持续注意力过程中的行为准确性以及总共 190 名健康受试者和 66 名精神分裂症患者接受奥氮平治疗 8 周后的反应。在健康受试者中，我们发现 DRD2 rs1076560 的 T 等位基因和 AKT1 rs1130233 的 A 等位基因之间的相互作用与 AKT1 蛋白水平降低和 GSK-3β 的磷酸化降低有关，还与扣带回响应改变和注意力处理过程中的行为准确性降低有关。另一方面，这两个等位基因的相互作用与奥氮平治疗后精神分裂症患者阳性和阴性综合征量表评分的更大改善有关。这些结果表明，这些功能多态性与与精神分裂症相关的多种表型存在上位性关联。我们的结果还支持进一步研究该下游分子途径在该疾病的病因和治疗中的作用。
