Weickert C S, Webster M J, Gondipalli P, Rothmond D, Fatula R J, Herman M M, Kleinman J E, Akil M
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, 9000 Rockville Boulevard, Building 10, CRC6-5340, Bethesda, MD 20892, USA.
Neuroscience. 2007 Feb 9;144(3):1109-19. doi: 10.1016/j.neuroscience.2006.10.009. Epub 2006 Nov 22.
Dopamine in the prefrontal cortex plays a critical role in normal cognition throughout the lifespan and has been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia and attention deficit disorder. Little is known, however, about the postnatal development of the dopaminergic system in the human prefrontal cortex. In this study, we examined pre- and post-synaptic markers of the dopaminergic system in postmortem tissue specimens from 37 individuals ranging in age from 2 months to 86 years. We measured the levels of tyrosine hydroxylase, the rate limiting enzyme in dopamine biosynthesis, using Western immunoblotting. We also examined the gene expression of the three most abundant dopamine receptors (DARs) in the human prefrontal cortex: DAR1, DAR2 and DAR4, by in situ hybridization. We found that tyrosine hydroxylase concentrations and DAR2 mRNA levels were highest in the cortex of neonates. In contrast, the gene expression of DAR1 was highest in adolescents and young adults. No significant changes across age groups were detected in mRNA levels of DAR4. Both DAR1 and DAR2 mRNA were significantly lower in the aged cortex. Taken together, our data suggest dynamic changes in markers of the dopamine system in the human frontal cortex during postnatal development at both pre-and post-synaptic sites. The peak in DAR1 mRNA levels around adolescence/early adulthood may be of particular relevance to neuropsychiatric disorders such as schizophrenia in which symptoms manifest during the same developmental period.
前额叶皮质中的多巴胺在整个生命周期的正常认知中起着关键作用，并且与精神分裂症和注意力缺陷障碍等神经精神疾病的病理生理学有关。然而，关于人类前额叶皮质中多巴胺能系统的产后发育情况，我们知之甚少。在本研究中，我们检查了37名年龄在2个月至86岁之间的个体的死后组织标本中多巴胺能系统的突触前和突触后标记物。我们使用蛋白质免疫印迹法测量了多巴胺生物合成中的限速酶酪氨酸羟化酶的水平。我们还通过原位杂交检测了人类前额叶皮质中三种最丰富的多巴胺受体（DARs）的基因表达：DAR1、DAR2和DAR4。我们发现，酪氨酸羟化酶浓度和DAR2 mRNA水平在新生儿皮质中最高。相比之下，DAR1的基因表达在青少年和年轻人中最高。在各年龄组中未检测到DAR4 mRNA水平有显著变化。在老年皮质中，DAR1和DAR2 mRNA均显著降低。综上所述，我们的数据表明，在产后发育过程中，人类额叶皮质中多巴胺系统标记物在突触前和突触后位点均发生动态变化。青春期/成年早期左右DAR1 mRNA水平的峰值可能与精神分裂症等神经精神疾病特别相关，因为这些疾病的症状在同一发育时期出现。
