Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition
Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition
复制标题
DOI：
10.1172/jci30413
复制
发表时间：
2007-03-01
影响因子：
15.9
通讯作者：
Weinberger, Daniel R.
中科院分区：
文献类型：
--
作者：
Meyer-Lindenberg, Andreas;Straub, Richard E.;Weinberger, Daniel R.
由PPP1R1B编码的多巴胺和camp调控的分子量为32 kDa的磷酸化蛋白（DARPP-32）是多巴胺感觉神经元中关键的信息整合者，调节对抗精神病药、拟精神药和滥用药物的反应，并影响纹状体功能和可塑性。尽管进行了大量的临床前工作，但几乎没有关于DARPP-32在人体中的功能的数据。在这里，我们通过对298条染色体的重测序，发现了一个常见的PPP1R1B单倍型，预测PPP1R1B同工型在死后人脑中的mRNA表达。这种单倍型与在依赖于前额纹状体功能的几个认知测试中的增强表现有关。健康受试者的多模态成像揭示了单倍型对新纹状体体积、激活和前额皮质功能连通性的影响。在1个基于家庭的关联分析中，单倍型与精神分裂症的风险相关。我们的研究结果确定了一个受PPP1R1B变异影响的前额叶-新纹状体系统，并表明DARPP-32在认知功能中起关键作用，可能在精神分裂症的发病机制中起关键作用。
Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on firontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia.