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
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 21228, USA.
Am J Med Genet B Neuropsychiatr Genet. 2009 Mar 5;150B(2):282-9. doi: 10.1002/ajmg.b.30811.
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.
平稳跟踪眼球运动（SPEM）缺陷是一种已确定的精神分裂症内表型，其神经认知结构与工作记忆相似。控制SPEM的额叶眼区（FEF）神经元在视觉感觉信息被去除时仍保持放电，其放电频率与SPEM速度直接相关。我们之前证明了多巴胺信号传导的功能多态性（COMT基因）与SPEM之间存在矛盾的关联。最近的证据表明多巴胺转运体基因（DAT1）在调节皮质多巴胺及相关神经认知功能中起作用。我们假设DAT1 10/10基因型，即降低多巴胺转运体表达并增加细胞外多巴胺，会影响SPEM。我们研究了DAT1基因型对以下方面的影响：研究样本（n = 418；190例精神分裂症患者）的临床诊断、完成眼动测量的亚组（n = 200；87例精神分裂症患者）的SPEM测量，以及从死后脑样本获得的FEF组织中DAT1基因的表达（n = 32；16例精神分裂症患者）。DAT1基因型与精神分裂症无关。DAT1 10/10基因型与健康对照者更好的SPEM、精神分裂症患者未受影响的一级亲属中等水平的SPEM以及精神分裂症患者较差的SPEM相关。在基因表达研究中，DAT1 10/10基因型与健康对照供体的FEF组织中DAT1 mRNA转录本显著降低相关（P < 0.05），但在精神分裂症供体中表达较高。研究结果表明精神分裂症中另一个基因或病因因素的调节作用，其调节DAT1基因功能。
