Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany.
Cereb Cortex. 2013 Jun;23(6):1453-62. doi: 10.1093/cercor/bhs132. Epub 2012 May 22.
The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder). DRD4 and COMT epistatically interacted on the NGA, whereas single genes and diagnosis showed no significant impact. Subjects with presumably relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an inverted U-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose effects and mirrored by reaction time variability (non-significant after multiple testing correction). Combining previous theories of prefrontal DA functioning, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. Our findings might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function.
前额皮质在认知控制中起着重要作用，但目前尚不清楚单个基因和基因-基因相互作用（遗传上位性）如何影响神经和行为表型。多巴胺（DA）的可用性（“倒 U 型模型”）和兴奋性与抑制性 DA 受体刺激（“双重状态理论”）都与前额叶处理的重要原则有关。使用 Go-NoGo 任务和脑电图（114 名对照和 181 名注意力缺陷/多动障碍患者）分析儿茶酚-O-甲基转移酶（COMT；Val158Met）和 DA D4 受体（DRD4；48 bp VNTR）基因型对前额叶反应控制（NoGo 前极化，NGA）的行为和神经相关性的影响。DRD4 和 COMT 在 NGA 上表现出遗传上位性相互作用，而单个基因和诊断对其没有显著影响。具有相对较高 D4 受体功能（DRD4：没有 7R-等位基因）的受试者表现出 NGA 与 COMT 依赖性 DA 水平增加之间的倒 U 关系，而 D4 敏感性降低（7R）的受试者则表现出 U 关系。这种相互作用得到了 7R-等位基因剂量效应的支持，并通过反应时间变异性（经多次测试校正后无统计学意义）得到了反映。将前额叶 DA 功能的先前理论结合起来，中间 DA 水平的神经稳定性可能伴随着如果抑制性 DA 受体功能进一步降低，神经灵活性过度降低的风险。我们的研究结果可能有助于厘清前额叶（功能）障碍背后的多巴胺能机制的遗传基础。
