Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia.
Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia.
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DOI：
10.1002/ajmg.b.30811
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发表时间：
2009-03-05
影响因子：
2.8
通讯作者：
Thaker, Gunvant K.
中科院分区：
文献类型：
--
作者：
Wonodi, Ikwunga;Hong, L. Elliot;Stine, O. Colin;Mitchell, Braxton D.;Elliott, Amie;Roberts, Rosalinda C.;Conley, Robert R.;McMahon, Robert P.;Thaker, Gunvant K.
平滑追踪眼球运动（SPEM）缺陷是一种确定的精神分裂症内表型，具有与工作记忆相似的神经认知结构。当视觉感觉信息被去除时，控制SPEM的额叶眼野（FEF）神经元保持放电，并且它们的放电率与SPEM速度直接相关。我们以前证明了多巴胺信号传导（COMT基因）的功能多态性和SPEM之间的矛盾关联。最近的证据表明，多巴胺转运蛋白基因（DAT 1）在调节皮质多巴胺和相关的神经认知功能。我们假设DAT 1 10/10基因型，减少多巴胺转运蛋白的表达和增加细胞外多巴胺，将影响SPEM。我们研究了DAT 1基因型的影响：临床诊断的研究样本（n=418，190精神分裂症），SPEM措施在一个亚组完成眼科措施（n=200，87精神分裂症），和DAT 1基因表达FEF组织从死后的大脑样本（n=32，16精神分裂症）。DAT 1基因型与精神分裂症无相关性。DAT 1 10/10基因型与健康对照组中的SPEM较好、精神分裂症受试者未受影响的一级亲属中的SPEM居中、精神分裂症受试者中的SPEM较差相关。在基因表达研究中，DAT 1 10/10基因型与健康对照供体FEF组织中DAT 1 mRNA转录显著降低相关（p<0.05），但在精神分裂症供体中表达较高。研究结果表明，另一个基因或致病因素在精神分裂症中的调节作用，调节DAT 1基因的功能。
Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n=418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n=200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n=32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (p<0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function.
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DOI：
10.1002/ajmg.b.30572
发表时间：
2007-12-05
影响因子：
2.8
作者：
Brookes, Keeley J.;Neale, Benjamin M.;D'Souza, Ursula M.
通讯作者：
D'Souza, Ursula M.
影响因子：
10.6
作者：
Lipska, Barbara K.;Deep-Soboslay, Amy;Kleinman, Joel E.
通讯作者：
Kleinman, Joel E.
影响因子：
17.7
作者：
Akil, M;Pierri, JN;Lewis, DA
通讯作者：
Lewis, DA
影响因子：
--
作者：
Holzman, PS
通讯作者：
Holzman, PS
影响因子：
--
作者：
Hong, LE;Mitchell, BD;Thaker, GK
通讯作者：
Thaker, GK